Tylenol on Trial: Does Acetaminophen Cause Autism and ADHD?

By Teresa Carr, Undark Magazine

More than 100 families of children with autism and attention deficit hyperactivity disorder are suing companies that market acetaminophen, the pain reliever in Tylenol and an array of other medications. Tylenol-maker Johnson & Johnson, as well as major retailers that use acetaminophen in their store-brand products, knew about research linking prenatal use of acetaminophen to neurodevelopmental disorders in children, the families claim, and should have included warnings on product labels.

The court filings reveal mothers wracked with guilt, convinced that by taking an over-the-counter pain reliever, they caused their child’s disability. In case after case, these women say that if they had thought acetaminophen could possibly harm their baby, they would have minimized their use of the drug — or not taken it at all.

It’s hardly an open-and-shut case. Most of what is known about acetaminophen and pregnancy comes from a type of study that sifts through data looking for correlations between prenatal exposures and developmental disorders. Scientists have been fighting amongst themselves over how much weight to give these studies, which were not designed to prove that a given factor — in this case, acetaminophen — caused ADHD or autism.

The debate reached a boiling point in 2021, when a group of international scientists declared that the current research, limited as it is, warrants stronger warnings about the use of acetaminophen during pregnancy. In a consensus statement published in Nature Reviews Endocrinology, the scientists called for “precautionary action” through focused research and increased awareness of the drug’s potential risks. Ninety-one scientists, clinicians, and public health professionals from around the world signed on.

That statement was the “galvanizing incident” for the lawsuits, said Ashley Keller, a founding partner at the legal firm Keller Postman LLC and one of the lawsuits’ lead attorneys.

‘An Outlier Opinion’

But there’s a hitch: The consensus statement does not, in fact, reflect the views of many experts or of any major medical organization. The same Nature journal published three rebuttals signed by numerous professional groups as well as individual researchers and clinicians. These critics wrote that the consensus statement used flawed data to exaggerate potential harms of acetaminophen and downplayed the drug’s essential role for treating fever and pain.

Johnson & Johnson has seized on those criticisms in its defense. The consensus statement “is an outlier opinion of a small group whose position has been rejected by their own medical organizations and every regulatory body to address the issue,” company spokesperson Melissa Witt told Undark in an email. Giving credence to theories not based in sound science, she said, could harm millions of pregnant women.

This debate over how to interpret the acetaminophen science lies at the heart of the lawsuits, and the answer has profound implications, both for individuals and for public health. Acetaminophen is one of the most common drugs in the world, and in the United States, up to 65 percent of all expectant mothers use it. The cases have been consolidated in the Southern District of New York. If the litigation proceeds to trial, attorneys expect tens to hundreds of thousands of families to join in.

It’s a shame that questions linger about the safety of a drug that’s been around for 70 years, said Christina Chambers, a professor of pediatrics at the University of California, San Diego and lead investigator for a series of studies on exposures during pregnancy for the Organization of Teratology Information Specialists, a professional society that provides advice on using medications during pregnancy and breastfeeding.

In an interview with Undark, Chambers expressed doubts about the consensus statement, saying that if acetaminophen has any effect on fetal development, that effect is likely to be modest. Still, she added, “What this accumulated data calls for is to do better study.”

Top Selling Pain Reliever

Acetaminophen was discovered in 1878, according to an FDA history of groundbreaking medications. But it wasn’t until the early 1950s that researchers demonstrated that the compound worked as well as the two popular pain relievers of the time — aspirin and acetanilide — with fewer side effects. In 1955, drugmaker McNeil gained FDA approval and launched Tylenol Elixir for Children, advertising it “for little hotheads.”

Four years later Johnson & Johnson acquired McNeil, and, in 1975, began aggressively marketing an “extra strength” 500-milligram version of the drug to adults. By the early 1980s, Tylenol was the top-selling pain reliever in the U.S.

Acetaminophen is now used in more than 600 over-the-counter and prescription medications, including combination products for sleep, cough, cold, and allergy.

Acetaminophen is one of the most common drugs in the world, and in the United States, up to 65 percent of all expectant mothers use it.

Today, new medications typically undergo toxicity testing in animals before researchers study their safety and effectiveness in humans, but like many older drugs, acetaminophen didn’t undergo as thorough of a process. “Back in ’55 we weren’t doing preclinical testing for reproductive safety,” said Chambers.

Scientists do know that, in most cases, acetaminophen is the safest way for pregnant women to relieve fever and pain. “Not treating a fever — especially a high fever — can have consequences,” continued Chambers.

Strong data from lab animal and human studies have associated a high fever at certain points in pregnancy with an increased risk of birth defects and other fetal abnormalities. And, while it’s an understudied area, she said, chronic pain is associated with depressive symptoms, insomnia, and other harms to the mother and could adversely affect her pregnancy.

Some common over-the-counter drugs treat both fever and pain, such as nonsteroidal anti-inflammatory drugs like aspirin, ibuprofen (Advil), and naproxen (Aleve), but the FDA warns against using any of these after 20 weeks of pregnancy because these drugs can damage the unborn babies’ kidneys.

Meanwhile, other painkillers have their own drawbacks. Babies exposed to opioids during the first trimester of pregnancy are at increased risk for birth defects of the brain, spine, and spinal cord. In addition, studies show that regular use of opioids during pregnancy increases the risk of poor fetal growth, preterm delivery, stillbirth, and neonatal opioid withdrawal syndrome.

Medicinal cannabis may address pain, and some women might think of it as a natural and, therefore, safe alternative. But there’s very little data available on short- and long-term outcomes for mothers and babies exposed to the potent products available today, said Chambers. Recent studies suggest that cannabis increases the risk of preterm birth and smaller babies, but it’s hard to tease out the effects from other factors. She described the drug’s legalization and increased societal acceptance as “a huge experiment happening now.”

“So, what are you left with?” she asked.

In 1975, Johnson & Johnson began aggressively marketing extra-strength Tylenol to adults. In this 1983 commercial, the product is touted as the most potent pain reliever that can be bought without a prescription:

Rising Rates of Autism and ADHD  

For pregnant people experiencing fever or pain, acetaminophen is widely viewed as the best option. But can it also harm the fetus?

To begin answering this question, researchers have analyzed preexisting datasets of health information, looking for associations between acetaminophen use during pregnancy and neurodevelopmental problems in children. Such research is referred to as observational, and while it can be useful, this approach can’t typically prove causality.

Autism rates have climbed steadily since the Diagnostic and Statistical Manual of Mental Disorders, or DSM, first established it as a distinct disorder in 1980. In 2000, 1 in 150 children were diagnosed with autism by the age of eight according to the Centers for Disease Control and Prevention; by 2020, the number had risen to 1 in 36.

ADHD rates increased as well, though not as sharply. In 2019, 6 million children between the ages of 3 and 17 (9.8 percent) had received a diagnosis of ADHD, compared to 4.4 million children in 2003, according to CDC data from a national survey of parents.

Many experts attribute the bulk of that increase to greater awareness and broadening definitions of the disorders. Factors such as improved survival for premature infants and a trend toward starting families later may also play a role, as both prematurity and older parents are associated with increased risk for neurodevelopmental disorders.

In the early 2010s researchers additionally became interested in whether acetaminophen, so commonly used by pregnant people, could affect fetal development.

In 2014, after a couple of observational studies suggested a possible link, the Food and Drug Administration began a formal process to track data on the issue. The findings from the agency’s initial review of the evidence, based on limited and contradictory data, were inconclusive according to a Drug Safety Communication published the following year.

Since then, researchers from several countries, including the U.S., have published a steady stream of observational research. In 2021, an international group of researchers came together to review the evidence and craft a consensus.

“We all sat down and said, it’s time to put all this together; we’ve done reviews, there’s more and more evidence,” said lead author Ann Bauer, an epidemiologist at the University of Massachusetts Lowell. “We all felt that it was time for women to have this information.”

Of the 29 observational studies involving 220,000 mother-child pairs, 26 linked prenatal use of acetaminophen to neurodevelopmental disorders including ADHD, autism, language delays, lower IQ, and cerebral palsy among others. Sixteen studies showed a more-pronounced effect with longer-term use of the drug.

Bauer pointed out that a handful of observational studies published after the consensus statement also suggest an association.

The group conceded that the observational data is imperfect. The positive association could stem from other factors, such as heredity or the condition that prompted the woman to take the drug. Still, the researchers concluded that the combined weight of the data was strong enough to warrant warning labels on acetaminophen and for health care professional to caution women against indiscriminate use of the drug. Society should act now, they wrote, “not wait unequivocal proof that a chemical is causing harm to our children.”

In science, it’s always possible to find something wrong with individual studies, said David Møbjerg Kristensen, a professor of molecular biology at Roskilde University in Denmark, one of the consensus authors. “But it’s more when you have all the studies lining up that you begin to be concerned,” he said.

‘Irresponsibly Published’

But other experts say that it’s misleading to stack up profoundly limited data and conclude that, as a whole, it carries more weight.

The paper from Bauer’s team was “irresponsibly published,” said Nathaniel DeNicola, an obstetrician-gynecologist based in Orange County, California, who helped review the evidence for the American College of Obstetricians and Gynecologists. “It did not reflect the preponderance and overall weight of the data, and it did not reflect the clinical context.”

DeNicola, who has expertise in environmental exposures and health policy, pointed out that consensus authors didn’t include numerous reviews, including those from major medical organizations, that drew different conclusions. Both ACOG and the Society for Maternal-Fetal Medicine, for example, found no clear evidence that acetaminophen causes fetal developmental issues and no reason to change current medical advice and practice.

In the end, neither did the FDA. In 2018, the agency brought the issue before its Medical Policy and Program Review Council, which provides oversight and direction of policies. The council found the available data didn’t warrant changes on acetaminophen labels or updates to the existing safety communication, wrote FDA press officer Charlie Kohler in an email to Undark.

While the agency continues to monitor the issue, it closed the formal tracking process in 2020 said Kohler, because extensive reviews failed to turn up solid evidence of a link between the drug and neurodevelopmental issues.

The gold standard for understanding the effect of a medication is to randomly assign one group to take the drug and another to get a placebo, with neither researchers nor participants knowing who got what until the end of the study. However, those randomized clinical trials rarely include pregnant women because of potential risks to the fetus. As a result, acetaminophen researchers rely on observational studies and laboratory experiments, including those that test the effects of the drug on experimental animals.

It can be difficult, however, to study neurodevelopmental problems in these animals. For one, researchers wouldn’t diagnose ADHD or autism in a mouse, though some research finds that mice exposed to acetaminophen in the womb are more likely to have problems with learning, memory, motor skills, and social behavior. Additionally, the biological mechanisms that lead to a diagnosis in humans are complex and not well understood, said Kristensen, so researchers don’t know what to exactly look for when they study the brains of laboratory animals.

Research in test tubes and lab animals does show that acetaminophen affects several chemical systems involved in brain development. “The compound is doing multiple different things during development at specific time points when the fetus is vulnerable,” said Kristensen. But whether these factors contribute to neurodevelopmental problems, he added, is unclear. Kristensen said that he expects to publish data within the next year or so that could help clarify the connection.

It’s also hard to know what to make of the observational research, which has numerous limitations, according to DeNicola. Many of the studies rely on women’s recall of having taken acetaminophen, which can be faulty weeks and even months later, he said. And instead of a clinical diagnosis of a child’s developmental or behavior disorder, studies often depend on assessments by parents and teachers, which sometimes differ.

One of the biggest issues with the observational research is failing to adequately control for other factors that cause autism and ADHD, particularly heredity, said Per Damkier, head of research in clinical pharmacology at the University of Southern Denmark and a co-author of a consensus rebuttal by the European Network of Teratology Information Services. (Teratology is the study of diseases and conditions that are congenital, or present at birth.) Based on data from Western countries, researchers estimate that up to 80 percent of autism and up to 90 percent of ADHD results from genes children inherited from their parents. If you don’t account for that huge factor, he said, “you inevitably will come up with misleading results.”

For example, a 2017 Pediatrics study included in the original consensus review found that the father’s use of acetaminophen increased a child’s risk of ADHD just as much as the mother’s use during pregnancy. While the researchers theorize that acetaminophen could have altered how the fathers’ genes work, Damkier said that the more likely explanation is that the analysis didn’t sufficiently adjust for heredity.

The pain or illness that prompts a woman to take a pain reliever may also skew the data. In their consensus rebuttal, authors from the Organization of Teratology Information Specialists point to the OTIS’ long-running MotherToBaby study, which found that compared to pregnant women who use acetaminophen for short periods, those who take it longer term report having more mental health conditions, including depression and anxiety, and are more likely to take antidepressants — all factors studies suggest are associated with ADHD and autism in children.

In a 2020 study, epidemiologist Reem Masarwa, then a postdoctoral fellow at McGill University in Montreal, and colleagues explored whether confounding factors such as heredity and maternal illness could be biasing acetaminophen research.

The group reanalyzed data from a meta-analysis Masarwa had published two years earlier, which had found a 35 percent increased risk of ADHD in children exposed to prenatal acetaminophen. This time the researchers stringently adjusted for parental ADHD and migraines in the mother.  The ADHD risk nearly disappeared.

‘There’s Something Biological Going On’

The consensus authors cite two studies that overcome the limitation of relying on a mother’s memory of acetaminophen use. The first, a 2019 study, tested umbilical cord blood for traces of acetaminophen and the second, published in 2020, measured acetaminophen in babies’ first bowel movement. Both found that the higher the prenatal exposure to acetaminophen, the greater the chance of a child receiving a physician diagnosis of a neurodevelopmental disorder.

“The beautiful thing about the new studies coming out is that the better the study, the stronger the associations,” said Kristensen. “Suddenly, you can see dose response, which is something we always look for because that argues that there’s something biological going on.”

However, both of those studies have drawbacks as well. Acetaminophen only lingers in the blood for a few hours, so the implication of the cord-blood study is that a single dose right before birth could have a dramatic effect on a child’s brain. Many experts find that result implausible.

Testing a newborn’s bowel movement may be a better measure as it is thought to reflect the mother’s use of acetaminophen during the last two trimesters of pregnancy. But as with some other observational studies, the researchers didn’t account for why the mother took the drug in the first place.

Plaintiff attorney Ashley Keller said that his first responsibility is to help his clients win compensation. In addition, he said, there’s also a public health issue at stake in that the women need full information to make informed decisions.

In April, U.S. District Judge Denise Cote, who is presiding over the pre-trial proceedings, took the unusual step of inviting federal regulators to provide an opinion on whether the science warrants adding a warning to acetaminophen labels about an association between prenatal exposure and ADHD and autism.

The FDA declined to comment on whether the agency would weigh in by the end of July as requested by Judge Cote.

Claiming that FDA regulations and federal laws prevent them from changing Tylenol labels, Johnson & Johnson is pushing for a dismissal. The company continues to evaluate the science and has not seen any evidence that acetaminophen use during pregnancy causes fetal development issues, Witt, the company spokesperson, wrote in an email. “Leading medical organizations agree with the current product label which clearly states, ‘If pregnant or breast-feeding, ask a health professional before use.’”

Bauer said the lawsuits are helping get the word out about the accumulating research on acetaminophen’s risks. Up until now, she said, a lot of women have viewed the drug as “completely innocuous,” something to take “whenever they are in discomfort.” Others disagree. DeNicola said that the women he sees in his practice are conscientious about using acetaminophen.

One thing everyone agrees on is the recommendations for acetaminophen use, said DeNicola: “Use it only where indicated in the lowest dose for the shortest duration.” So, for pain or fever that means taking one pill, one time, to see if symptoms ease, he said.

Another point of real consensus is the need for more research. Bauer said that several groups are looking at possible mechanisms for how acetaminophen could affect development. “As far as the epidemiology, there’s a pretty perfect study that could be done,” she said, pointing out that, with smartphones, women can easily record what they take and why. “But it’s going to take us many, many years is the problem.”

“Something that is potentially this important for, not just fetal, but for childhood brain development should be studied,” DeNicola said. “And it should be studied in a real way.” For example, he would like to see studies that use blood tests and other measures throughout pregnancy to accurately track exposures not just to acetaminophen, but also to environmental substances of greater concern to fetal development, such as industrial chemicals. And, since a baby’s brain continues to develop after birth, studies should account for use of acetaminophen in childhood — a glaring omission from most of the current research, said DeNicola.

At the moment, no one is conducting exactly that type of study on acetaminophen.

However, FDA spokesperson Charlie Kohler said that agency is conducting a small study to see how people’s bodies absorb, metabolize, and excrete the drug. The agency is also planning a toxicology study in 2024, pending approval of funding.

And Chambers said that she is coordinating a study funded by the National Institutes of Health of about 8,000 mother-child pairs in 25 sites across the U.S. The Healthy Brain and Child Development Study will capture information on prenatal exposures, including to acetaminophen, and use brain imaging and standardized assessments to track brain development in children. Researchers will release data annually, so information on prenatal exposure to acetaminophen will begin to emerge in the next couple of years, she said.

If there’s anything good to come out of the controversy, it’s that every drug, over the counter or not, deserves rigorous research on safety, said Chambers — and society hasn’t invested in systematically doing that type of research. She pointed out that while the FDA requires new drugs to be assessed for safety during pregnancy, nobody has the resources of motivation to do that for old drugs like acetaminophen.

“And we need to stop that,” said Chambers. “We need to turn that wheel around, pay attention and do the work that needs to be done.”

This article was originally published by Undark, a non-profit, editorially independent online magazine covering the complicated and often fractious intersection of science and society. You can read the original article here.

Home Delivery of Rx Opioids Would Help Chronic Pain Patients

By Pat Anson, PNN Editor

We hear almost every day from people in pain who say they can’t get an opioid prescription filled because their pharmacy is out of stock. Often, the pharmacist has no idea when the next shipment of pain medication is coming.

“Walgreens cannot fill my prescription. They say the drug is on back order with no ship date available,” a patient recently told us.

“20 years on the same Rx for Vicodin and now CVS says they are out of stock and no idea when it will be available,” another patient wrote.

“Just talked to a pharmacist today that said they are out of Percocet, Vicodin and morphine. They said that their supplier, Cardinal Health, wasn't sure when they would get more,” said another patient.

Now imagine, if you will, what it would be like to have a pharmacy that delivers opioid medication directly to your home. No more standing in line at the pharmacy. No more dirty looks from the pharmacist. No more excuses about being out of stock.

For about 1,000 patients in the Philadelphia area, most of them chronic pain sufferers, that fantasy is a reality. They are customers of a boutique pharmacy in the Delaware Valley that specializes in home deliveries of controlled substances – including high dose opioids.  Prescriptions and refills are delivered on a carefully managed schedule before a patient runs out, becomes disabled by uncontrolled pain, and goes into withdrawal.

“We hand deliver directly to the patient. I have a whole delivery team. They're our own drivers, our own vehicles,” says Brian Dunleavy, CEO of PMC Pharmacy. “Our customers get notified when their delivery is anticipated to arrive at their home. And then every patient has to sign for it. They have to be present or we can't leave it there. Or it has to be an adult that's been authorized to receive the medication.”

I first heard of PMC Pharmacy when it sent out a news release last month to address difficulties that some patients have getting opioids and other controlled medications from other pharmacies in the Delaware Valley. PMC said it could help those patients avoid gaps in drug therapy and was committed to keeping them “on schedule, at home, and independent.”

“We should really have every chronic pain management patient in the Delaware Valley under our care because of the way our program works,” Dunleavy told PNN.

While big chain pharmacies and their wholesale drug suppliers are under increased scrutiny from law enforcement and regulators, PMC flies under the radar because its customers’ medical conditions, prescriptions and insurance claims are carefully documented – reducing the risk of diversion or misuse.     

“We won't take patients from a typical primary care practice, we're only working with chronic pain specialists who give us (patient) chart notes and supporting documentation to satisfy our wholesalers’ desires that we're doing due diligence on all these doctors and all these patients, and making sure that there's a legitimate need for the medication,” Dunleavy explained. “The diversion isn't coming from the people that are legitimate chronic pain patients. Those people hold onto that medication as if it's their lifeline.”

Trifecta of Problems

The supply of opioids and other controlled substances is tight because of a trifecta of problems that have hamstrung the pharmaceutical industry.

First, the Drug Enforcement Administration has been aggressively cutting opioid production quotas for nearly a decade, reducing the supply of oxycodone by 65% and hydrocodone by 73% since 2013.

Second is the fallout from opioid litigation. The nation’s three largest drug wholesalers reached a $21 billion settlement with 46 states, requiring them to impose strict limits on opioid shipments to pharmacies. CVS, Walgreens and other pharmacy chains have also paid tens of billions of dollars to settle lawsuits that alleged they helped fuel the overdose crisis by dispensing too many opioids.  

The third reason for tight supplies is a retooling of the generic drug industry. There’s little money to be made in selling most opioids and there’s a risk of further liability, so drug makers are cutting back production of many generic opioids.  One of the world’s largest manufacturers of generics, Teva Pharmaceutical, recently notified the FDA that it was discontinuing production of oxycodone.

It all adds up to an increasing number of drug shortages, involving not just opioids, but medications used to treat cancer, anxiety and attention deficit disorder. Dunleavy thinks the shortages are a direct result of regulatory overreach.

“You have all these things going on and everybody's like, ‘Oh well, there's a shortage of oxycodone out there.’ And in actuality, there isn't. It's a regulatory created shortage, which is why there's a discrepancy between what we're hearing from patients versus what we see at the on the wholesalers’ shelves,” he explained. “The pharmacies can't get those drugs because they're quantity restricted by the wholesalers, based on the programs that the wholesalers have implemented to police the pharmacies.”

Dunleavy says PMC would like to add more patients to its customer base, provided they live in its delivery area in southeastern Pennsylvania and parts of New Jersey and Delaware that border Philadelphia. He’s confident he’ll be able to get the additional medication from suppliers.

“You're not going to have a better adherence and compliance program from a pharmacy than ours,” he said. “Because our program is pain management specific, once we start working with a practice, we start getting quite a few referrals. So it's very easy for us to start growing.”

Could PMC’s business model be adopted by other pharmacies? With pain management under so much scrutiny, Dunleavy says home deliveries to selected patients make sense.

“There's a legitimate need for a pharmacy that puts in a little bit more effort, that's a little bit more specialized. Because the regulatory environment requires it, the patients require it, and the physicians require it,” he said.

“This is a very interesting concept. It almost sounds too good to be true, but if it really works it would be tremendously helpful to many chronically ill people,” says Kristen Ogden, a patient advocate in Virginia. “I think this concept may be really helpful to house-bound patients and persons with limited access to transportation, especially those who don't have an engaged family member helping them.”  

For many years, Kristen and her husband Louis have traveled to California to get the high dose opioids he needs to treat severe pain from arachnoiditis and Ehlers-Danlos Syndrome. Not having to make that monthly cross-country trip for refills would be a welcome relief to the Ogdens.  

“It would be great to think this sort of service would be available to us as we get older, especially since we have no children and no other family members who live in our area to assist us. This could certainly be a big factor in enabling older adults to continue living in their own homes if that's what they prefer to do,” Kristen said. 

The American Society of Health-System Pharmacists put immediate release oxycodone on its list of drug shortages in March and added hydrocodone/acetaminophen tablets to the list in May.  Neither shortage has yet to be recognized by the FDA, although many patients are already well aware that both medications are in short supply. 

“I've been waiting for over a week for oxycodone to come in. Over the last weekend, I went to over 25 different pharmacies searching, until I couldn't drive anymore. It's not fair to any of us!” a pain patient recently told PNN

Patients Squeezed in Fight Over Costly Infusion Drugs

By Samantha Liss, KFF Health News

Health insurers and medical providers are battling over who should supply high-cost infusion drugs for patients, with the tussle over profits now spilling into statehouses across the country.

The issue is that some insurers are bypassing hospital pharmacies and physician offices and instead sending more complex drugs through third-party pharmacies. Those pharmacies then send the medications directly to the medical provider or facility for outpatient infusing, which is called “white bagging,” or, more rarely, to patients, in what is called “brown bagging.” That shifts who gets to buy and bill for these complex medications, including pricey chemotherapy drugs.

Insurers say the policies are needed because hospital markups are too high. But hospitals argue that adding an intermediary results in unnecessary risks and delays, and they say some insurers have their own or affiliated pharmacy companies, creating financial motives for controlling the source of the medications. The patients, meanwhile, are left to deal with the red tape.

Paula Bruton Shepard in Bolivar, Missouri, is among those caught in the middle. Flares of lupus, an autoimmune disease, rob Shepard of her mobility by attacking her joints. She relies on monthly infusions to treat her symptoms.

PAULA SHEPARD

But at times, she said, her treatments were delayed due to UnitedHealthcare’s white bagging infusion policy. And interruptions to her treatments exacerbated her symptoms.

“I once had to use a toilet lift and it was kind of demoralizing to say, ‘I’m a 50-year-old woman and I have to use a toilet lift,’” Shepard said of the medication delays.

This is a tug of war over profits between insurers and medical providers, said Ge Bai, a professor of accounting and health policy at Johns Hopkins University. While insurers claim the arrangement reduces costs, she said, that doesn’t mean insurers pass along savings to patients.

“I don’t think we should have more sympathy toward one party or the other,” Bai said. “Nobody is better than the other. They’re all trying to make money.”

The savings from white bagging can be significant for expensive infusion drugs, according to a report from the Massachusetts Health Policy Commission. For example, Remicade, used to treat a variety of inflammatory diseases, including Crohn’s, cost on average $1,106 per unit in 2015 under hospitals’ traditional buy-and-bill system, the commission found in its review of state claims data. That same drug cost an average of $975 per unit under white bagging, a 12% savings.

But the report also found patients, on average, faced higher cost sharing — what they are responsible for paying — for Remicade and other drugs when white bagging was used. While some patients had only modest increases to their costs under the policy, such as $12 more for a medication, the review found it could mean much greater cost sharing for some patients, such as those on Medicare.

Delays in Care

At Citizens Memorial Hospital in rural Bolivar, more than 1 in 4 patients who receive regular infusions are being forced to use an outside pharmacy, said Mariah Hollabaugh, the hospital’s pharmacy director. Shepard was among them.

Even if the hospital has the exact drug on the shelf, patients must wait for a separate shipment, Hollabaugh said, potentially interrupting care. Their shipped drugs may sometimes be unusable when the doctor needs to change the dosage. Or the medicine comes in a nondescript package that doesn’t get immediately flagged for the pharmacy, potentially subjecting the drugs to damaging temperature fluctuations. For patients, that can mean delays in care.

“They’re in pain, they’re uncomfortable,” Hollabaugh said. “They may be having symptoms that don’t allow them to go to work.”

Siteman Cancer Center, led by physicians from Washington University School of Medicine in St. Louis, has confronted the same issue. But the cancer center’s size has helped it largely avoid such insurer policies.

John DiPersio, a Siteman oncologist and researcher who led the university’s oncology division for more than two decades, said Siteman reluctantly allows white bagging for simple injectables but refuses to accept it for complicated chemotherapies. It does not accept brown bagging. Occasionally, he said, that means turning patients away.

“You’re talking about cancer patients that are getting life-threatening treatments,” DiPersio said, referring to the dangers of chemo drugs, which he said can be fatal if used improperly. “It doesn’t make any sense to me. It’s all stupid. It’s all lunacy.”

At least 21 states, including Missouri, introduced some form of white or brown bagging legislation during the most recent legislative session, according to the American Society of Health-System Pharmacists. And in the past two years, the trade group said, at least 13 states have already enacted restrictions on white bagging, including Arkansas, Louisiana, and Virginia.

ASHP has created model legislation to limit insurers from requiring the practices as a condition of coverage.

“This is a major issue,” said Tom Kraus, a vice president at the trade group. “We see this as central to our ability to coordinate patient care.”

At the heart of the tension is an often-litigated federal program that allows certain hospitals and the clinics they own to purchase drugs at deep discounts. The 340B program, named for a section of the law that created it, allows hospitals to buy certain drugs for much less — sometimes for a total cost of a single penny — than what they are later paid for those drugs. Hospitals are not required to pass along 340B savings to patients.

The program was intended to help hospitals spread scarce resources further to treat patients in poor and vulnerable communities, but it has morphed into a means of enriching hospitals and their affiliated clinics, researchers said in a 2014 Health Affairs report. Hollabaugh said many rural facilities such as Citizens rely on the revenue generated from the 340B drugs to subsidize infusions that have no profit margin.

The number of participating hospitals and their affiliated outpatient clinics has increased significantly since the 340B program was created in 1992. More than 2,600 of the nation’s roughly 6,100 hospitals were participating in the 340B program as of January 2023. That gives them access to discounts that can knock off as much as 50% of a drug’s cost, according to the Health Resources & Services Administration, which oversees the program.

‘People Got Greedy’

The insurance industry argues that hospital markups, especially when made on top of those discounts, have gotten out of control.

“The fact is, people got greedy,” Shannon Cooper, a lobbyist for Blue Cross and Blue Shield of Kansas City, said during a Missouri state Senate hearing in March.

Markups are not unique to 340B hospitals, said Sean Dickson, who helps lead pharmaceutical policy for AHIP, a trade group formerly known as America’s Health Insurance Plans. The markups thrusted on commercial plans are “widely out of line” with what Medicare will pay, he said, and that is driving up costs without providing additional value.

Legislation that targets white bagging hinders an insurer’s ability to rein in such costs, Dickson said, especially when an area lacks competition.

“What we're really trying to focus on here is putting pressure on those markups that are not related to cost or safety,” Dickson said.

Anthem Blue Cross and Blue Shield lobbyist David Smith testified during the March hearing in Missouri that even the idea of white bagging elicited a quick response and that almost every major hospital system in the state said they would drop their prices and come back to the negotiation table.

For now, Citizens Memorial Hospital and other Missouri medical facilities will have to continue to tango with the insurers: Legislation to limit white and brown bagging did not pass during the Missouri General Assembly’s recent session.

Shepard, though, won’t need such legislation.

UnitedHealthcare had been sending her lupus infusion through other pharmacies on and off since 2021, unwilling to cover the drugs if they came from Citizens’ in-house pharmacy. Shepard had to authorize each shipment before it was sent. If she missed the monthly call, she said, it was a “bureaucratic mess” trying to get the medication shipped.

“We are driving unnecessary costs out of the health care system to help make care more affordable, while also maintaining drug safety, effectiveness and quality of care,” UnitedHealthcare spokesperson Tony Marusic wrote.

But after KFF Health News inquired about Shepard’s case, Marusic said UnitedHealthcare stopped white bagging Shepard’s medication to “prevent potential delays in shipping.” And during her latest infusion in June, her hospital was again able to supply Shepard’s medication directly.

“I'm just so relieved,” Shepard said. “I don't have to take phone calls. I don't have to reply to emails. I just show up.”

KFF Health News is a national newsroom that produces in-depth journalism about health issues.

Millions of People Worldwide Are ‘Left Behind in Pain’

By Pat Anson, PNN Editor

A new report by the World Health Organization (WHO) warns that limited access to morphine and other opioids is leaving millions of people in many parts of the world suffering in preventable pain.

The report, “Left Behind in Pain,” calls morphine a low cost, essential medicine for relieving moderate to severe pain. But access to morphine and other opioids is inadequate in many low and middle-income countries, with consumption patterns in wealthier nations that don’t correspond to medical need. Over 95% of the world’s supply of opioids is distributed in wealthy countries, with only 0.03% distributed in low-income ones.

“Leaving people in pain when effective medicines are available for pain management, especially in the context of end-of-life care, should be a cause of serious concern for policy-makers,” says Yukiko Nakatani, MD, WHO Assistant Director-General for Medicines and Health Products. “We must urgently advocate for safe and timely access to morphine for those in medical need through balanced policy, everywhere.”

The report calls for expanded access to morphine through local and regional distribution centers, changes in restrictive laws and guidelines, and reduced stigma surrounding opioid use.

“Some historical events, cultural beliefs, misinformation and disinformation about pain, and social stigma related to opioid use are known to have caused mistrust of opioids and contributed to fear of using them,” the report found.

Lawsuits and regulatory controls on the pharmaceutical industry are so strong in some countries that drug makers have stopped manufacturing morphine because the profit is low and risk of liability is high.

That may have played a role in Mundipharma’s recent decision to discontinue supplying Ordine, a liquid formulation of morphine, to Australia. Mundipharma is owned by the Sackler family, which has been enmeshed in opioid litigation over its role in the opioid crisis in the U.S. through its operation of Purdue Pharma.

A Mundipharma spokesperson told the Australia Broadcasting Corporation that the company’s third-party manufacturer decided to stop producing Ordine and that "sourcing another manufacturer would not be commercially viable."

Evolving Stance on Opioids

WHO’s position on opioids has evolved over the years. WHO’s guidelines for treating chronic pain, for example, used to say that opioids “are known to be safe and there is no need to fear accidental death or dependence.”

That changed in 2019, after two U.S. congressmen – without any real evidence -- accused WHO of being “corruptly influenced” by opioid manufactures. WHO withdrew the guidelines a month later, citing “new scientific evidence” – although critics said caved in to political pressure and threats to withdraw U.S. funding of WHO.

In 2021, WHO backpedaled further, recommending that morphine only be given to sick children when they are dying. Physical therapy and “biopsychosocial” treatments such as cognitive behavioral therapy were suggested as alternatives for children who are in pain, but expected to live.

WHO’s latest report recognizes the potential harms of opioids, couched in language about the world facing two opioid crises.

“The world is facing two crises related to the use of opioids. In the first, inappropriate use and over-prescription combined with the wide availability of illicit unregulated opioids, such as fentanyl, in some countries is causing significant harm and loss of life. In the second, a lack of access to opioids such as morphine in many parts of the world means that millions of people continue to suffer preventable pain,” said Nakatani.

About 80% of the world’s morphine supply was consumed in North America in 2021, primarily in the United States, although the rest of the developed world is catching up. Opioid consumption in the U.S. has fallen so sharply in recent years that Canada, Australia and several European countries have become the highest consumers of opioid analgesics, according to a 2022 study that ranked the U.S. as being 8th in per capita opioid sales.

Restoring Safe Supply of Rx Opioids Would Reduce Overdoses

By Pat Anson, PNN Editor

A decade long effort to reduce the supply of opioid pain medication in the U.S. has contributed to a surge in overdose deaths and made the illicit drug supply more toxic, according to a new study.

“A big reason that we have such a problem with addiction in this country is because people can't access legitimate pain medication,” said lead author Grant Victor, PhD, an assistant professor at Rutgers University School of Social Work. “Our findings support a change in policy.”

Victor and his colleagues analyzed toxicology data from nearly 2,700 accidental overdose deaths in the Indianapolis metropolitan area (Marion County, Indiana) from 2016 to 2021, comparing them to patient records in the state’s prescription drug monitoring program (PDMP).

Their findings, published in the Journal of Substance Use and Addiction Treatment, show that less than half the people who overdosed (43.3%) had any kind of PDMP record, meaning they were never prescribed an opioid pain reliever or buprenorphine (Suboxone), a medication used to treat opioid use disorder.

Most of the decedents who did have a prescription for an opioid analgesic or buprenorphine had not filled one in the 30 days prior to their deaths, indicating that prescription opioids are not driving overdose deaths in Marion County. Overdoses there increasingly involve illicit fentanyl, a synthetic opioid 100 times more potent than morphine, which accounts for nearly 90% of the county’s overdoses.  

There were 637 drug deaths in Marion County in 2021, nearly twice the number that died in 2016. During that period, opioid prescriptions in the county fell by nearly a third.

MARION COUNTY PUBLIC HEALTH DEPT.

Toxic Drug Market

Victor says many of the overdose deaths could have been prevented if a safer supply of prescription opioids was still accessible – both to legitimate patients and those who misuse the drugs.

“There was a wave of policy initiatives that effectively tamped down on the diversion of prescription opioids, but did so primarily by increasing surveillance of prescribing practices for opioids. And through a number of mechanisms, that made it more difficult for individuals with legitimate pain concerns to access these types of medications,” Victor told PNN.

“When you remove a certain class of drugs that is federally regulated and can be monitored and dosed appropriately, it leaves folks with few options. Options that are currently available are illicit and the potency of these drugs is highly variable. The drug market in general, as we know it today, is very toxic and that is one of the main drivers in the overdose crisis.”

Victor says some of his own family members have chronic pain and after years of taking opioids safely, they’ve been cutoff and told to take Tylenol. He said it’s rare for a pain patient to die from an overdose and few meet the diagnostic criteria for substance use disorder.   

“There are a number of researchers who are trying to drive this point home and hope to reverse some of the policy initiatives that have unfolded over the last few years that have been perhaps unintentionally harmful to public health and to chronic pain patients,” he said.

“We've been swept up in this kind of frenzy about prescription opioids. They're still making movies about the Sackler’s (owners of Purdue Pharma). My opinion of them is not all that high, but I think it is a convenient kind of scapegoat to portray pharmaceutical companies as the evil here, when they’re not a primary concern. When you're looking at public health and what's currently driving overdose deaths, it’s not prescription opioids.”

Few previous studies have compared overdose deaths directly to prescription drug data, which would seem to be an obvious way to get to the bottom of what’s causing the overdose crisis.  One such study looked at opioid overdoses in Massachusetts, finding that only 1.3% of those who died had an active prescription for opioids.

Low Dose Opioids Ineffective for Acute Lower Back and Neck Pain

By Pat Anson, PNN Editor

A low dose of prescription opioids works no better than a placebo in relieving acute lower back or neck pain, according to a new study in Australia.  

The blinded, placebo-controlled trial was relatively small – just 345 participants – but was unusual because patients were followed for up to a year, a rarity for a clinical trial that studies pain.  Half the participants received a combination of oxycodone and naloxone for six weeks at a low daily dose of 20mg or about 30 morphine milligram equivalents (MME). The other half received placebo tablets that looked similar to oxycodone.   

It's important to note that the study only included people with mild or moderate pain of less than 12 weeks duration -- not the severe, long-term back and neck pain caused by degenerative disc disease, spinal injuries, arthritis, and other chronic conditions. Participants were excluded if they had that type of pain.  

The study findings, published in The Lancet, showed no significant difference in pain severity between the opioid and placebo groups. On a scale of zero to 10, the average pain score was 2.8 in the opioid group after six weeks, compared to 2.3 in the placebo group. After a year, the average pain score was 2.4 in the opioid group, versus 1.8 in the placebo group. 

Pain Severity Over 52 Weeks

THE LANCET

Researchers say patients who received opioids had a slightly higher risk of opioid misuse at the end of the study, a finding based on a mental health survey that screens patients for drug related behavior.

“Our findings show that even judicious, short-term use of an opioid conferred no benefits in pain reduction and led to a small increase in pain at the medium-term and long-term compared with placebo. The opioid group had worse quality-of-life mental health scores than the placebo group,” researchers reported. “Although no difference was found in overall time to recovery, more people in the placebo group recovered in the first 14 days compared with those in the opioid group.”

Most medical guidelines recommend exercise and over-the-counter pain relievers for short-term back or neck pain, with opioids only used as a last resort. The authors of the Lancet study say even that limited use is inappropriate.

“Opioids should not be recommended for acute back and neck pain, full stop,” said lead investigator Christine Lin, PhD, a professor in the School of Public Health at University of Sydney. “Not even when other drug treatments are not able to be prescribed or have not been effective for a patient.”

The Lin study is somewhat similar to the 2018 Krebs study, which found that low doses of oxycodone were no more effective than over-the-counter pain relievers in treating chronic back and osteoarthritis pain. Critics say the Krebs study was biased from the start and this one is no better.

“They generalise enormously,” Michael Vagg, MD, Dean of Pain Medicine at the Australian and New Zealand College of Anaesthetists, told the Medical Republic. “They studied oxycodone and naloxone in a modified-release formulation. But modified-use opioids have never been on-label for use in acute pain and they are not recommended as such… to which I and everyone in pain medicine would say ‘We figured that out ages ago’. That’s not how you use opioids in acute pain.

“In layman’s terms, they’ve done a study where they tried to look at doing push-ups to help with back pain and then they’ve decided that all exercise is no good for the back pain.”

Lower back pain is the world’s leading cause of disability and neck pain is the fourth largest, but there is surprisingly little evidence about the best ways to treat them.

A previous study published in The Lancet by an international team of researchers found that lower back pain was often treated with bad advice, inappropriate tests, risky surgeries and painkillers. The authors said there was limited evidence to support the use of opioids for low back pain, and epidural steroid injections and acetaminophen (paracetamol) were not recommended at all. Most patients responded better to physical and psychological therapies that kept them active.

Australian Guideline Calls for Safer Opioid Tapering

By Pat Anson, PNN Editor

Public health experts in Australia have released what is being called the first international guideline to help primary care doctors safely reduce or stop prescribing opioids to adults with chronic non-cancer pain.

The Guideline for Deprescribing Opioid Analgesics contains 11 recommendations developed by a panel of general practitioners, pain specialists, addiction specialists, pharmacists, nurses and physiotherapists. The guideline emphasizes slow and individualized tapering for patients when long-term opioid use does not improve their pain and quality of life or when they experience adverse side effects. Tapering is not recommended for anyone nearing the end-of-life.

“Internationally, we were seeing significant harms from opioids, but also significant harms from unsolicited and abrupt opioid cessation. It was clear that recommendations to support safe and person-centred opioid deprescribing were required,” said lead author Aili Langford, PhD, a pharmacist and Research Fellow at Centre for Medicine Use and Safety, Monash University.

Millions of pain patients in the U.S. were tapered or cut off cold turkey after the CDC released its 2016 opioid prescribing guideline. Both the American Medical Association and the FDA warned that rapid tapering was causing “serious harm” to patients, including withdrawal, uncontrolled pain, substance abuse and suicide.

In response to that criticism, the revised 2022 CDC guideline took a more cautious approach to tapering, recommending a dose reduction of just 10% a month, a much slower rate than the 10% a week that the agency previously recommended.

The U.S. Department of Veterans Affairs and Department of Defense (VA/DoD) also modified their approach to tapering, which at one time called for tapers of up to 20% every four weeks.  The updated VA/DoD guideline says there is “insufficient evidence to recommend for or against any specific tapering strategies.”

The Australian guideline doesn’t get caught up in fractions or percentages. It simply calls for “gradual tapering” that is tailored to each patient’s needs and preferences. A key recommendation is to discuss tapering as early as possible with patients, to develop a plan when they are first prescribed opioids.  

“Shared decision-making and ensuring that patients have ways to manage their pain are essential when a deprescribing plan is being discussed,” said Liz Marles, MD, a general practitioner and clinical director at the Australian Commission on Safety and Quality in Health Care.  

“These new guidelines further support appropriate use of opioid analgesics and how to safely prescribe and stop prescribing them. They ask clinicians to consider reducing or stopping opioids when the risk of harm outweighs the benefits for the individual.”

One in five adults in Australia have chronic pain, but few actually wind up taking opioids long-term. The guideline authors estimate that only 5% of opioid “naive” patients become long-term users, well below misleading claims by anti-opioid activists that over 25% of pain patients develop opioid dependence or opioid use disorder.

“I am curious to know how many people who are on chronic opioid therapy feel a need to be tapered,” said Lynn Webster, MD, a pain management expert and Senior Fellow at the Center for U.S. Policy.  “Only 5% of opioid-naïve patients remain on opioids for 3 months or longer. Considering the fact that about 10% of the population has severe enough pain to affect quality of life, this statistic argues against the theory that just being exposed to an opioid leads to chronic opioid use.”

Webster says most of the recommendations in the Australian guideline are practical, but he’s concerned that some of the evidence used to support them is “misunderstood and misleading.”

“They make it abundantly clear that tapering should not be forced and that there are serious consequences to forced tapering. But they also use the common yet flawed statement that there is little evidence that opioids are effective for chronic non-cancer pain. Of course, the lack of evidence is not evidence,” Webster said.

Although opioids have been used for thousands of years for pain relief, the clinical evidence for or against their use remains thin. Most of the evidence used to support the Australian guideline was deemed by the authors to be insufficient, unclear or weak. Only one of the 11 tapering recommendations was supported by evidence of “moderate certainty.”

Burden of Pain: How the CDC and DEA Criminalized Medicine

(Jay K. Joshi, MD, is a primary care physician in Indiana who spent nearly a year in prison after pleading guilty to prescribing opioids without a “legitimate medical need” to an undercover DEA agent who was posing as a pain patient. Joshi now regrets that guilty plea and is trying to vacate his conviction due to alleged DEA misconduct.

While in prison, Joshi began writing “Burden of Pain: A Physician’s Journey through the Opioid Epidemic.” His book is a cautionary tale about misguided public health policy and overzealous law enforcement, which often portray doctors as drug dealers and patients as addicts.

PNN editor Pat Anson recently spoke with Joshi, who is practicing medicine again and hopes to regain his license to prescribe opioids. This interview has been edited for content and clarity.)

JAY K. JOSHI, MD

Anson: Dr. Joshi, who is your book intended for and what is the main message you're trying to send?

Joshi: The book really is for the general public and those that have a vested interest in helping to rectify misguided federal policy, as it pertains to not just the opioid epidemic, but the overdose crisis as a whole.

My main message is that we have to understand that healthcare has a lot of uncertainty and complexity. And if we just use simplified rubrics, like cookie cutter medical guidelines or restrictive laws, we're going to create unintended consequences. It's time that we start to re-examine clinical decisions and health policy as a whole, so that we can make better informed decisions.

Anson: Do you think the general public has a good understanding of the opioid crisis and what caused it? Or is there misinformation going around that they've bought into?

Joshi: I would say there's a strong degree of misrepresentation among policymakers, who should have known better before and certainly should know better now. I think the narrative of opioid prescriptions running amok and creating this overdose crisis is a story that’s taken on a life of its own.

Did prescription opioids contribute to the overdose crisis that we see now? Yes. Was it the main driving factor? No. But there were trends in drug use and drug policy through the 2000’s and 2010’s that falsely conflated prescription opioids with illicit opioids. Policymakers should now understand that there are fundamental differences in how opioids are abused versus how they're used in a proper clinical setting.

Anson: Given what's transpired over the last few years, with overdoses soaring from illicit fentanyl and opioid prescriptions declining, do you think policymakers now know better?

Joshi: You know, in life as a general rule of thumb, often you learn more about what a person doesn't say, than what they do say. And this kind of hollow resonance in connecting fentanyl overdoses to previous manifestations of the overdose crisis to me is a glaring omission of responsibility from federal policymakers at the CDC level and law enforcement at the DEA and state level.

They’ve failed to acknowledge that the current fentanyl crisis is a manifestation of restrictive and overly simplified opioid policies that began nearly a decade ago. And I think the fact that people are not correlating that when the data clearly shows it indicates there is a willful understanding and a willful intent to not accept responsibility for prior failures and opioid policies.

Anson: Do you think the CDC and the DEA made the fentanyl crisis worse?

Joshi: It's difficult to say because when you use the word “worse,” then you almost have to apply some sort of causality. I like to look at the overdose crisis a little differently.

Did the CDC with their opioid policy guidelines contribute to the trends and overdoses that we're seeing now? Yes. By not recognizing that the guidelines would be codified into law and policy, and deliberately affect clinical decision making. They're not taking accountability for all the damaging effects. So, by that logic, you can say the CDC made the opioid epidemic worse.

But I would instead reframe it to say the CDC needs to better educate itself. What you see from them is a conflation of words, reflecting a lack of proper understanding. That's how I would define the revised 2022 CDC opioid prescribing guideline.

They talk a lot about nuances. They talk a lot about “uncertainty,” although not using that word as much as I believe that they should. But then eventually they revert to the same policy trend of creating overly simplified stipulations using morphine milligram equivalents (MME) as this rubric of clinical care, even though it was never intended to be used as a clinical decision-making tool.

The CDC needs to be better aware of its own conflicts of interest in the leadership making policy decisions. We can go down line by line looking at these individuals and assessing their conflicts of interest. And I certainly have seen things that would be quite alarming for anybody who values scientific objectivity.

But I feel like when you go down that pathway, you're simply entrenching people in their own lease, meaning the CDC will simply double down and say,”No, what we're doing is right” and the DEA will simply double down and say,” No, what we're doing is right.”

Anson: Do you think the CDC should even have an opioid guideline?

Joshi: It is odd that a public health organization would get involved with something that has, for all intents and purposes, a direct patient to physician relevancy. It's hard for me to understand how the CDC initially thought that when the guidelines made it a public health issue. It was almost as if it became a self-fulfilling prophecy.

The CDC felt like prescription opioids were a public health issue, and therefore created guidelines that affected the patient-physician relationship, thereby creating undue stigmatization in a clinical encounter that should otherwise be based upon a foundation of trust and respect.

And by doing so, they almost exacerbated the overdose crisis into a public health issue. It's very difficult to understand why they felt like those guidelines would help, as opposed to focusing on keeping prescription opioids within the framework of the patient-physician encounter, as it already had been.

I guess they were looking at rising overdose rates and conflated illicit opioids, heroin and fentanyl with prescription opioids. I'm not sure where that direct line of logic really came from. It's difficult to really justify that.

Anson: And what about the DEA? As you very well know, a lot of doctors have stopped prescribing opioids or have really scaled back the doses that they give to patients, because they don't want to go to prison like you did.

Joshi: Definitely, and I can understand that. What's interesting is that I've had direct engagements with DEA officers, and from my perspective they lack the necessary understanding of prescription opioids and the benefit it provides patients. They lack the healthcare context.

What the DEA does is correlate the clinical encounter with what you would see in a routine drug transaction. In their eyes, having a hammer as the only tool, everything looks like a nail. So the drug dealer in Mexico running Chinese products through a drug cartel entering the United States is cognitively equivalent to a physician treating patients with chronic pain.

They don't have the ability to discern context and the role clinical need plays in how patients are treated. And I think that really does an injustice to both the patients and the physicians, because effectively the only tool the DEA has to address prescription opioid use is fear. And when you use fear in the clinical context, you’ve harmed the most vulnerable patients. It's a shame that the DEA is not acknowledging this.

I wrote an op/ed in Medpage Today about a month ago, in which I asked the DEA to take a stance on harm reduction. Many medical societies talk about how harm reduction is a better overall policy to help patients. But medical societies are not implementing the laws, the DEA is implementing the laws.

So regardless of how high-minded the policies may be, unless implementation of the policies aligns with intent, you're not going to have patients being treated the way that they should be. And I think what the DEA really needs to do is to assess its role in the clinical encounter and make honest determinations on whether they have the capabilities to understand clinical need for opioids as it pertains to patients with chronic pain or acute pain. I think the DEA is lacking in that capacity.

Anson: Is the DEA practicing medicine? They say they don't.

Joshi: I know. And I disagree. I would say that the DEA is very much involved in the practice of medicine. If you are influencing clinical decisions through fear, you are engaging in the practice of medicine.

What is clinical medicine? If you present to me with headache and vision changes, and I checked your vitals and see that you have extremely high blood pressure, I'm going to consider you as somebody in hypertensive crisis. I'm making that decision based upon the facts presented to me and then, based upon that decision, I will implement a certain form of treatment. Clinical medicine is a series of decisions made in the face of uncertainty.

Should I trust my blood pressure monitor that the readings are correct? Should I trust you when you say that you have a headache and vision changes? How much of that uncertainty is simply assumed to be true when any clinical decision is made?

Now, the moment you incorporate fear into that clinical decision making, you're influencing how the decisions are made and the eventual course of clinical action.  So very much the DEA is practicing medicine, and I would greatly appreciate if they were honest about that.

Anson: You've obviously given this a lot of thought and, at the same time, you don't sound that bitter about what happened to you. Why is that?

Joshi: You know, when I was in federal prison, I was extremely depressed. I lost my medical practice. I lost my freedom. But I always felt like, in the end, things would turn out right and the truth would come out. Whether that was a delusional belief sitting in a federal prison, I don't know. But I held onto that belief.

It's through that belief that I improved my writing abilities and hand wrote the first version of “Burden of Pain.” It’s through that belief that I regained my medical license and was reinstated as a Medicare provider.

I don't feel bitter because I feel that I have a responsibility to patients and to physicians who might be going through similar situations. And if I can behave in a certain way that is productive, that can turn what I went through into an overall good for patients and for society as a whole, then I’ll feel like what I went through was worth it.

“Burden of Pain” and other books are featured in PNN’s Suggested Reading section.

DEA Ending Lenient Telehealth Rules in November

By Arielle Zionts, KFF Health News

Federal regulators want most patients to see a health care provider in person before receiving prescriptions for potentially addictive medicines through telehealth — something that hasn’t been required in more than three years.

During the COVID-19 public health emergency, the Drug Enforcement Administration allowed doctors and other health care providers to prescribe controlled medicine during telehealth appointments without examining the patient in person. Controlled medications include many stimulants, sedatives, opioid painkillers, and anabolic steroids.

The emergency declaration ended May 13, and in February, the agency proposed new rules that would require providers to see patients at least once in person before prescribing many of those drugs during telehealth visits.

Regulators said they decided to extend the current regulations — which don’t require an in-person appointment — until Nov. 11 after receiving more than 38,000 comments on the proposed changes, a record amount of feedback. They also said patients who receive controlled medications from prescribers they’ve never met in person will have until Nov. 11, 2024, to come into compliance with the agency’s future rules.

The public comments discuss the potential effects on a variety of patients, including people being treated for mental health disorders, opioid addiction, or attention-deficit/hyperactivity disorder. Thousands of commenters also mentioned possible impacts on rural patients.

Opponents wrote that health care providers, not a law enforcement agency, should decide which patients need in-person appointments. They said the rules would make it difficult for some patients to receive care.

Other commenters called for exemptions for specific medications and conditions.

Supporters wrote that the proposal would balance the goals of increasing access to health care and helping prevent medication misuse.

Special Referrals for Rural Patients

Zola Coogan, 85, lives in Washington, Maine, a town of about 1,600 residents northeast of Portland. Coogan has volunteered with hospice patients and said it’s important for very sick and terminally ill people in rural areas to have access to opioids to ease their pain. But she said it can be hard to see a doctor in person if they lack transportation or are too debilitated to travel.

Coogan said she supports the DEA’s proposed rules because of a provision that could help patients who can’t travel to meet their telehealth prescriber. Instead, they could visit a local health care provider, who then could write a special referral to the telehealth prescriber. But she said accessing controlled medications would still be difficult for some rural residents.

“It could end up being a very sticky wicket” for some patients to access care, she said. “It’s not going to be easy, but it sounds like it’s doable.”

Some health care providers may hesitate to offer those referrals, said Stefan Kertesz, a physician and professor at the University of Alabama at Birmingham whose expertise includes addiction treatment. Kertesz said the proposed referral process is confusing and would require burdensome record-keeping.

Ateev Mehrotra, a physician and Harvard professor who has studied telehealth in rural areas, said different controlled drugs come with different risks. But overall, he finds the proposed rules too restrictive. He’s worried people who started receiving telehealth prescriptions during the pandemic would be cut off from medicine that helps them.

Mehrotra said he hasn’t seen clear evidence that every patient needs an in-person appointment before receiving controlled medicine through telehealth. He said it’s also not clear whether providers are less likely to write inappropriate prescriptions after in-person appointments than after telehealth ones.

Mehrotra described the proposed rules as “a situation where there’s not a clear benefit, but there are substantial harms for at least some patients,” including many in rural areas.

Beverly Jordan, a family practice doctor in Alabama and a member of the state medical board, supports the proposed rule, as well as a new Alabama law that requires annual in-person appointments for patients who receive controlled medications. Jordan prescribes such medications, including to rural patients who travel to her clinic in the small city of Enterprise.

“I think that once-a-year hurdle is probably not too big for anybody to be able to overcome, and is really a good part of patient safety,” Jordan said.

Jordan said it’s important for health care practitioners to physically examine patients to see if the exam matches how the patients describe their symptoms and whether they need any other kind of treatment.

Jordan said that, at the beginning of the pandemic, she couldn’t even view most telehealth patients on her computer. Three-fourths of her appointments were over the phone, because many rural patients have poor internet service that doesn’t support online video.

The proposed federal rules also have a special allowance for buprenorphine, which is used to treat opioid use disorder, and for most categories of non-narcotic controlled substances, such as testosterone, ketamine, and Xanax.

Providers could prescribe 30 days’ worth of these medications after telehealth appointments before requiring patients to have an in-person appointment to extend the prescription. Tribal health care practitioners would be exempt from the proposed regulations, as would Department of Veterans Affairs providers in emergency situations.

Many people who work in health care were surprised by the proposed rules, Kertesz said. He said they expected the DEA to let prescribers apply for special permission to provide controlled medicine without in-person appointments. Congress ordered the agency to create such a program in 2008, but it has not done so.

Agency officials said they considered creating a version of that program for rural patients but decided against it.

Denise Holiman disagrees with the proposed regulations. Holiman, who lives on a farm outside Centralia, Missouri, used to experience postmenopausal symptoms, including forgetfulness and insomnia. The 50-year-old now feels back to normal after being prescribed estrogen and testosterone by a Florida-based telehealth provider. Holiman said she doesn’t think she should have to go see her telehealth provider in person to maintain her prescriptions.

“I would have to get on a plane to go to Florida. I’m not going to do that,” she said. “If the government forces me to do that, that’s wrong.”

Holiman said her primary care doctor doesn’t prescribe injectable hormones and that she shouldn’t have to find another in-person prescriber to make a referral to her Florida provider.

Holiman is one of thousands of patients who shared their opinions with the DEA. The agency also received comments from advocacy, health care, and professional groups, such as the American Medical Association.

The physicians’ organization said the in-person rule should be eliminated for most categories of controlled medication. Even telehealth prescriptions for drugs with a higher risk of misuse, such as Adderall and oxycodone, should be exempt when medically necessary, the group said.

State Laws Burden Patients

Some states already have laws that are stricter than the DEA’s proposed rules. Amelia Burgess said Alabama’s annual exam requirement, which went into effect last summer, burdened some patients. The Minnesota doctor works at Bicycle Health, a telehealth company that prescribes buprenorphine.

Burgess said hundreds of the company’s patients in Alabama couldn’t switch to in-state prescribers because many weren’t taking new patients, were too far away, or were more expensive than the telehealth service. So Burgess and her co-workers flew to Alabama and set up a clinic at a hotel in Birmingham. About 250 patients showed up, with some rural patients driving from five hours away.

Critics of the federal proposal are lobbying for exemptions for medications that can be difficult to obtain due to a lack of specialists in rural areas.

Many of the public comments focus on the importance of telehealth-based buprenorphine treatment in rural areas, including in jails and prisons.

Rural areas also have shortages of mental health providers who can prescribe controlled substances for anxiety, depression, and ADHD. Patients across the country who use opioids for chronic pain have trouble finding prescribers.

It also can be difficult to find rural providers who prescribe testosterone, a controlled drug often taken by transgender men or people with various medical conditions, such as menopause. Controlled medications are also used to treat seizures, sleep disorders, and other conditions.

KFF Health News is a national newsroom that produces in-depth journalism about health issues.

Drugmakers Are Abandoning Cheap Generics

By Arthur Allen, KFF Health News

On Nov. 22, three FDA inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck.

Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.

Seven months later, doctors and their patients are facing the unimaginable: In California, Virginia, and everywhere in between, they are being forced into grim contemplation of untested rationing plans for breast, cervical, bladder, ovarian, lung, testicular, and other cancers. Their decisions are likely to result in preventable deaths.

Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, attention-deficit/hyperactivity disorder pills, blood thinners, antibiotics and opioids. Covid-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry.

Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.

The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures — undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.

But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?

“It’s just insane,” said Mark Ratain, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”

“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, an oncologist in Hot Springs, Arkansas, who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin.

Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.

“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during covid; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”

The 10 cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives — though sometimes less effective and often with more side effects — are available. But some doctors are even rationing doses intended to cure.

Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.

“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”

Brent McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family — his other daughter, Cate, made a TikTok video about her sister’s plight — were simply stunned at such a basic flaw in the health care system.

At Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.

ISABELLA MCDONALD AND HER FATHER, BRENT

On June 2, Moore and her colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale — only with mortal consequences at stake.

She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”

Doses remained at 80%, she said. Things hadn’t changed 10 days later.

Generics Manufacturers Are Pulling Out

The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.

As generics manufacturers compete to win sales contracts with the big buyers, including wholesale purchasers Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February.

Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Teva notified the FDA earlier that month that it was discontinuing production of oxycodone tablets, a move that could exacerbate shortages of opioid pain medication.   

Lannett Co., with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.

The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said.

Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.

Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market.

Sardella, the Washington University professor, testified last month that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions. The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.

Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.

Asked why it waited two months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”

Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-milligram bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at Moore’s clinic.

“It’s hard to have these conversations with patients — ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, chair of the Department of Obstetrics, Gynecology and Reproductive Health at Rutgers New Jersey Medical School.

Should Government Step In?

Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.

As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.

Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm, she said. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”

More lasting solutions are under discussion. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.

“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Virginia, that will produce dozens more, Coukell said.

Ratain and his University of Chicago colleague Satyajit Kosuri recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.

In fact, Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store two years’ worth of carboplatin and cisplatin.

“It would almost literally be a drop in the bucket.”

KFF Health News is a national newsroom that produces in-depth journalism about health issues.

Patients Who Received Opioids During Surgery Had Better Outcomes

By Pat Anson, PNN Editor

As pressure grows on the Biden Administration to implement the NOPAIN Act and require Medicare to pay higher costs for non-opioid pain relievers during surgery, a new study shows that restricting the use of opioids during surgical procedures may do more harm than good.

Researchers at Massachusetts General Hospital (MGH) analyzed the health records of over 61,000 patients who had surgery under general anesthesia at MGH, and found that those who received opioids were less likely to experience post-operative pain and needed fewer opioids during recovery.

The study findings, published in in JAMA Surgery, showed that surgery patients who were given the opioids fentanyl and hydromorphone had less pain, lower rates of persistent opioid use, and fewer opioid prescription refills. They were also less likely to have chronic pain 12 months after surgery.

Researchers were particularly surprised to find that patients who received higher doses of fentanyl had fewer chronic pain diagnoses and needed fewer opioid prescriptions 30, 90 and 180 days after surgery.

“We were surprised by the extent to which intraoperative administration of opioids was associated with medium- and long-term outcomes. This may relate to the fact that if inadequate amounts of opioids are administered in the operating room, patients may emerge from general anesthesia in pain, a phenomenon that has a known association with persistent postsurgical pain,” wrote lead author Patrick Purdon, PhD, Department of Anesthesia, Critical Care, and Pain Medicine at MGH.

“The main implication of this study is that in the drive toward overall reduction of opioid usage in surgical pain management in the US, the role of intraoperative nociception in determining postoperative pain may have been overlooked to the detriment of patient outcomes.”

Researchers say their findings underscore the importance of ensuring that patients don’t emerge from general anesthesia in pain, not only for their short-term wellbeing, but to prevent long-term opioid use.

“The opioid crisis is a major motivator for mitigating the risks of opioid usage,” said co–first author Laura Santa Cruz Mercado, MD, an anesthesiology resident at Beth Israel Deaconess Medical Center and former research fellow at MGH. “But appropriate opioid administration in the operating room may reduce total opioid usage after surgery.”

Lobbying for Early Implementation of NOPAIN

Although previous studies have found that the risk of opioid misuse or overdose after surgery is rare, pressure on U.S. hospitals to reduce their use of opioids has resulted in a 50% decrease in opioid prescribing after surgery.  

Supporters of the NOPAIN Act would like it to decrease further and faster. Passed by Congress late last year, the Act requires the Centers for Medicare and Medicaid Services (CMS) to expand reimbursement policies for non-opioid treatments in outpatient surgical settings, starting in 2025. Supporters of the bill have launched a campaign to have the timetable moved up to 2024.

“Healthcare leaders must help CMS understand the inevitable damage that will result if the agency does not implement the policy in 2024. Millions of Americans will be put needlessly at risk of opioid addiction for another year,” Nirav Amin, MD, an orthopedic surgeon at Pomona Valley Hospital in Pomona, CA, wrote in a recent op/ed in Healthcare Dive. “The policy will incentivize greater use of non-opioids by creating separate reimbursements for the administration of these therapies.”

Unmentioned in Amin’s column is that he’s been paid over $360,000 in recent years as a consultant for Pacira BioSciences, a company that stands to directly benefit from the NOPAIN Act. Pacira makes Exparel, an expensive injectable formulation of bupivacaine, a non-opioid analgesic used to treat post-operative pain.

Bupivacaine is a generic drug that only costs about $35 a vial, while Exparel is priced 10 times higher, at $365 a vial. According to two recent studies that Pacira claimed were “false and misleading,” Exparel works no better than the much cheaper bupivacaine products.

Pacira has made over $32 million in various payments to Amin and other doctors to help promote Exparel, according to Open Payments, a CMS database that tracks industry payments to healthcare providers. Pacira is also bankrolling Voices for Non-Opioid Choices, an advocacy group that is leading the campaign for early implementation of the NOPAIN Act.

Pacira is also very active politically, spending over $2.6 million on lobbying and campaign donations since 2018, according to OpenSecrets. In 2019, Pacira hired former New Jersey governor and current presidential candidate Chris Christie as a consultant for $800,000 and lucrative stock options. At the time, Christie had recently chaired President Trump’s opioid commission, which recommended that Medicare and Medicaid reimbursement policies be changed to encourage hospitals to use more non-opioid pain relievers.

Chemotherapy and Opioid Shortages Impacting Cancer Care

By Pat Anson, PNN Editor

Over two-thirds of cancer centers in the U.S. are reporting shortages of methotrexate and other drugs used in chemotherapy, according to a survey by the National Comprehensive Cancer Network (NCNN).

Methotrexate is a versatile drug that prevents cells from dividing. It was originally developed to treat cancer, but is also widely used to treat autoimmune and neurological conditions such as lupus, rheumatoid arthritis, migraine and multiple sclerosis.

The NCNN surveyed 27 cancer centers across the U.S. in late May, and found that 67% of them were reporting shortages of methotrexate. Most centers are also reporting chronic shortages of carboplatin and cisplatin, chemotherapy agents that are widely used in cancer treatment. The shortages have resulted in treatment delays or forced doctors to modify their treatment plans using other drugs.

"This is an unacceptable situation. We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now," Robert Carlson, MD, CEO of NCCN, said in a statement. "We were relieved by survey results that show patients are still able to get life-saving care, but it comes at a burden to our overtaxed medical facilities." 

Drugs shortages in the U.S. are currently near record levels, primarily due to shipping delays and other disruptions caused by the pandemic. But the shortage in chemotherapy agents largely stems from a halt in production at a plant in India operated by Intas Pharmaceuticals. FDA inspectors found quality-control violations at the plant late last year and the agency recently slapped an import alert on the company. The agency is working with drug makers in China to make up the difference.

The FDA added methotrexate injectable solution to its drug shortage list in March. Supplies are currently limited and the shortage is not expected to end until December 2023. No shortages are currently reported for methotrexate tablets.

Hydrocodone Shortage

In addition to chemotherapy drugs, some drug makers are also reporting shortages of opioid pain medication. The American Society of Health-System Pharmacists (ASHP) recently added hydrocodone-acetaminophen combinations – commonly known under the brand names Vicodin and Norco-- to its own drug shortage database.

Generic drug makers Amneal, Camber, KVK-Tech, Major and Rhodes currently report shortages of 5 mg, 7.5 mg, and 10 mg hydrocodone tablets. None of the companies provided a reason for the shortage or an estimate for when it might end. Many of the same drug makers reported shortages of oxycodone in March.

The limited supply of opioids is also affecting cancer patients. The University of Utah Health system recently informed its drug wholesaler that it was adding 50 new beds to its cancer clinic and would be needing more pain medication to treat the extra patients.

“And the wholesaler said, ‘Well, let's just wait until we start receiving your orders to increase the amounts that you're going to buy,’” said Erin Fox, PharmD, Senior Pharmacy Director at University of Utah Health, which tracks drug shortages for the ASHP. “We're unable to be proactive. We're trying to think ahead. And we don't want to have that situation where we we're getting very close to running out or not having enough. That's basically what our wholesaler says has to happen.”

“We wish that we could fix all these things, but we don't make the medicines and we can't tell someone that they must make medicines. There are some things that are out of our control,” FDA Commissioner Robert Califf, MD, said in a recent interview with Medscape.

The Drug Enforcement Administration, in consultation with the FDA, sets the annual production quotas for opioids and other controlled substances. The DEA reduced this year’s supply of oxycodone and hydrocodone by about 5 percent, after being advised by FDA that demand for Schedule II opioids would decline. Since peaking a decade ago, DEA production quotas have fallen by 65% for oxycodone and 73% for hydrocodone.

FDA Head Says Drug Shortages ‘Out of Our Control’

By Pat Anson, PNN Editor

With drug shortages in the U.S. near record levels, the head of the Food and Drug Administration says there is little his agency can do to ease shortages, particularly those involving generic drugs.

“We wish that we could fix all these things, but we don't make the medicines and we can't tell someone that they must make medicines. There are some things that are out of our control,” FDA Commissioner Robert Califf, MD, said in an interview with Medscape.  

There are currently 207 medications in short supply, according to the FDA’s drug shortage list, but the American Society of Health-System Pharmacists (ASHP) has a much higher estimate of over 300 active drug shortages, the most since 2014.

Shortages of generic medications used to treat cancer and attention deficit disorder (ADHD) have gotten the most attention, but there are also emerging shortages of generic oxycodone and other opioid pain medications. About 90% of prescribed drugs in the U.S. are low-cost generics.

“And this has caused a big problem, where a number of generic drugs are in shortage at any given time, because there's not enough profit for a company to say they want to go into the business of making that drug,” said Califf.

Teva Pharmaceutical, one of the world’s largest manufacturers of generic drugs, announced last month that it would change its business model to focus on more profitable branded drugs. Teva has already informed the FDA that it was discontinuing production of 30, 15, and 5 mg tablets of generic oxycodone.  

Another generic drug maker, Perrigo Pharmaceuticals, recently notified the FDA that it was stopping production of a cough syrup made with hydrocodone.

Pain patients have had trouble for years getting prescriptions filled for opioids, but the problem appears to have gotten more acute in recent months – and not just for generic opioids. Joy CobbWilliams told PNN she has trouble getting prescriptions filled for OcyContin, a branded formulation of oxycodone that she’s been taking for nearly a decade for chronic back pain.

“Month after month I run out of my medication while I wait for the pharmacy to get more. Some months I wait three or four days and other months I wait almost two weeks. The pain I suffer is unbearable,” she said. “Something needs to be done. We have got to do better for the patients suffering and not abusing the medication. This is the United States and there should be no reason someone suffering should have to wait days to weeks to get their 10mg OxyContin.” 

Kim Luarks told us she’s had problems with her pharmacy running out of fentanyl patches and Xtampza ER (oxycodone). She’s been on opioids for 20 years due to chronic back pain. 

“Here I sit, still waiting and have been without any long-acting opioid for (7 days) and not feeling too hot,” she said. “This could be detrimental to my life, let alone my heart and lungs that are already damaged due to the doctors just throwing pain meds at me in the early 2000’s. I've been through all the changes and federal regulations causing this nonsense.” 

The Drug Enforcement Administration, in consultation with the FDA, determines the annual production quotas for opioids and other controlled substances. Despite Califf’s contention that drug shortages are “out of our control,” it was the FDA that advised the DEA that demand for Schedule II opioids such as oxycodone would fall by 5.3% in 2023. 

DEA adopted the FDA’s recommendations and reduced the supply of opioids for the seventh consecutive year, saying it would be “sufficient to meet all legitimate needs.” Since their peak in 2013, DEA production quotas have fallen by 65% for oxycodone and 73% for hydrocodone.

In his interview with Medscape, Califf suggested that some medications are now in short supply not because of production quotas, but because they are prescribed to people who don’t really need them. He said stronger medical guidelines may be needed to discourage doctors from overprescribing.   

“If only the people that needed these drugs got them, there probably wouldn't be a shortage. There's a large amount of use which is on the margins. And this is why I say we need better clinical standards,” Califf said.

“But having said all that, we're working with the DEA frequently as they try to work out what the quotas are. And we're working with the companies to optimize production. So that shortage should go away. It's better now than it was a few months ago, and it's going to continue to get better.”

Studying Natural Opioids Could Lead to New Non-Addictive Analgesics

By Dr. John Streicher, University of Arizona

Opioid drugs such as morphine and fentanyl are like the two-faced Roman god Janus: The kindly face delivers pain relief to millions of sufferers, while the grim face drives an opioid abuse and overdose crisis that claimed nearly 70,000 lives in the U.S. in 2020 alone.

Scientists like me who study pain and opioids have been seeking a way to separate these two seemingly inseparable faces of opioids. Researchers are trying to design drugs that deliver effective pain relief without the risk of side effects, including addiction and overdose.

One possible path to achieving that goal lies in understanding the molecular pathways opioids use to carry out their effects in your body.

What Are Natural Opioids?

The opioid system in your body is a set of neurotransmitters your brain naturally produces that enable communication between neurons and activate protein receptors. These neurotransmitters include small protein-like molecules like enkephalins and endorphins. These molecules regulate a tremendous number of functions in your body, including pain, pleasure, memory, the movements of your digestive system, and more.

Opioid neurotransmitters activate receptors that are located in a lot of places in your body, including pain centers in your spinal cord and brain, reward and pleasure centers in your brain, and throughout the neurons in your gut. Normally, opioid neurotransmitters are released in only small quantities in these exact locations, so your body can use this system in a balanced way to regulate itself.

The problem comes when you take an opioid drug like morphine or fentanyl, especially at high doses, for a long time. These drugs travel through the bloodstream and can activate every opioid receptor in your body. You’ll get pain relief through the pain centers in your spinal cord and brain. But you’ll also get a euphoric high when those drugs hit your brain’s reward and pleasure centers, and that could lead to addiction with repeated use. When the drug hits your gut, you may develop constipation, along with other common opioid side effects.

Targeting Opioid Signals

How can scientists design opioid drugs that won’t cause side effects?

One approach my research team and I take is to understand how cells respond when they receive a message from an opioid neurotransmitter. Neuroscientists call this process opioid receptor signal transduction. Just as neurotransmitters are a communication network within your brain, each neuron also has a communication network that connects receptors to proteins within the neuron.

When these connections are made, they trigger specific effects like pain relief. So, after a natural opioid neurotransmitter or a synthetic opioid drug activates an opioid receptor, it activates proteins within the cell that carry out the effects of the neurotransmitter or the drug.

Opioid signal transduction is complex, and scientists are just starting to figure out how it works. However, one thing is clear: Not every protein involved in this process does the same thing. Some are more important for pain relief, while some are more important for side effects like respiratory depression or the decrease in breathing rate that makes overdoses fatal.

So what if we target the “good” signals like pain relief and avoid the “bad” signals that lead to addiction and death? Researchers are tackling this idea in different ways. In fact, in 2020, the U.S. Food and Drug Administration approved the first opioid drug based on this idea, oliceridine, as a painkiller with fewer respiratory side effects.

However, relying on just one drug has downsides. That drug might not work well for all people or for all types of pain. It could also have other side effects that show up only later on. Plenty of options are needed to treat all patients in need.

Inhibiting a Protein Relieves Pain

My research team is targeting a protein called Heat shock protein 90, or Hsp90, which has many functions inside each cell. Hsp90 has been a hot target in the cancer field for years, with researchers developing Hsp90 inhibitors as a treatment for many cancer types.

We’ve found that Hsp90 is also really important in regulating opioid signal transduction. Blocking Hsp90 in the brain blocked opioid pain relief. However, blocking Hsp90 in the spinal cord increased opioid pain relief. Our recently published work uncovered more details on exactly how inhibiting Hsp90 leads to increased pain relief in the spinal cord.

Our work shows that manipulating opioid signaling through Hsp90 offers a path forward to improve opioid drugs. Taking an Hsp90 inhibitor that targets the spinal cord along with an opioid drug could improve the pain relief the opioid provides while decreasing its side effects. With improved pain relief, you can take fewer opioids and reduce your risk of addiction. We are currently developing a new generation of Hsp90 inhibitors that could help realize this goal.

There may be many paths to developing an improved opioid drug without the burdensome side effects of current drugs like morphine and fentanyl. Separating the kindly and grim faces of the opioid Janus could help provide the pain relief we need without addiction and overdose. 

John Streicher, PhD, is an Associate Professor in the Department of Pharmacology at the University of Arizona. Dr. Streicher has published over 70 peer-reviewed articles and is engaged in numerous drug discovery campaigns to create new analgesics. He receives funding from the National Institutes of Health, the Arizona Biomedical Research Commission, the Flinn Foundation, and the University of Arizona.

This article originally appeared in The Conversation and is republished with permission.

My Life Is on the Line Due to Rx Opioid Shortages

By Christine Kucera, Guest Columnist

On May 24, I had my regularly scheduled pain management appointment. The prescription for my normal regimen of 10mg oxycodone was sent electronically to my local CVS pharmacy. About an hour later, I received a text from CVS saying they received the prescription from my doctor.

I followed up later through their automated system. That is the moment of shocking revelation when I learned that my prescription was not going to be filled on time, and that it may not be ready until a week after my fill date.

Utterly panicked, heart racing, thinking and speaking a mile a minute, I contacted the pharmacy. They confirmed they were out of 10mg oxycodone tablets.

“What am I supposed to do?” I asked. A woman who I don’t know replied that I should try contacting other pharmacies.

Really? I can’t do that. Pharmacies won’t tell me, the patient, if they have a supply of a controlled substance. So she looked it up and said it looks like “X” pharmacy has it and that I should have my doctor send the prescription there. Unfortunately, by the time my provider received the message, it was too late.

I made multiple calls to another pharmacy and they were extremely rude. I called my pharmacy again. This time I spoke with a pharmacist that knew me. He was very understanding, as we discussed what to do next.

CHRISTINE KUCERA

We came up with a plan. He said to have my doctor send him a prescription for 5mg oxycodone. I immediately emailed my provider about the shortage and asked him to send a new prescription for 5mg, since they were out of 10mg tablets.

It was a very long night and I was extremely anxious waiting for a reply from my provider. As a long-term opioid patient of 30 years with intractable pain, I’ve been through the unimaginable, especially after the CDC published its first opioid guideline. Since 2016, I’ve been force tapered to suboptimal treatment levels, denied pain medication during multiple hospitalizations, and told to take Tylenol.

A surgeon even used prescription fentanyl on me during an interventional procedure after being told it doesn’t work on me – leaving me awake and screaming during the procedure. That’s just to name a few examples. Believe me, there are many more.

My thoughts are racing out of control. I can’t do this anymore. I can’t live life with unrelenting, unmanaged pain all day, every day. I’m barely holding on now, trying hard not give up hope. It’s not easy living in a body that’s under assault from an invisible invader, leaving my entire body riddled with rare diseases, along with severe bone, nerve, connective tissue and organ pain.

As a person with severe medically induced PTSD, I can fully recall all of the previous times I was forced off my managed regime of opiate medication. This time it’s going to be at the hands of the DEA, which has intentionally created shortages of oxycodone.

Next day arrives, a new prescription for 5mg is sent and I sigh with relief. It was short lived. Another pharmacist said my insurance company won’t cover the 5mg substitute without prior authorization. Completely losing control of my emotions, I asked why do I need another prior authorization?  My daily limit of 90 morphine milligram equivalents (MME) didn’t change, just the dose of the tablets

“It’s because of daily quantity limits,” the pharmacist replied.

Are you freaking serious?  I’m out of oxycodone as of today and you’re saying I can’t have 2 weeks of a substitute because there is no supply anywhere of 10mg and my insurance has quantity limits on 5mg doses?  I was angry and upset. This is so wrong! What am I supposed to do?

To that, the pharmacist says, “You can pay out of pocket.”

I didn’t have a choice, although I knew what happens from paying out of pocket with cash and sending prescriptions to new pharmacies. Those are red flags for prescription drug monitoring programs (PDMPs).

What’s next CDC and DEA? You’ve fabricated the great Opioid Lie and created policies that affect all pain care in all settings. Created new burdens for disabled and chronically ill patients. Created an opioid guideline that doesn’t allow for individualized treatment and places limits on prescriptions. You’ve shackled doctors with no options but to provide inadequate pain care or abandon patients altogether.

Now patients and their providers are having to deal with DEA created shortages of essential medicines. This has got to stop! Pain patients have never been the driver behind the overdose crisis. Anti-opioid prohibition policies are harming, torturing and killing U.S. citizens.

What do I do? There are no protections or even a set of procedures in place to assist patients and providers when there are shortages of controlled substances. It really is a nightmare situation. I feel helpless. The shortage is not my fault, the restrictions have gone too far, and my life is on the line.

Christine Kucera lives with psoriatic arthritis, spondyloarthropy, spondylitis, polyarthritis, sacroiliitis, degenerative joint disease, dermatomyositis, mixed connective tissue disease, spinal radiculopathy, hypoparathyroidism, rare endocrine tumors, psoriasis, endometriosis stage IV, pelvic adhesive disease, and other painful conditions. 

Prior to becoming disabled, Christine was a healthcare research systems developer and analyst for federally funded CMS, AHRQ, and NIH grants and programs. 

Do you have a “My Story” to share? Pain News Network invites other readers to share their stories about living with pain and treating it. We are particularly interested in your experiences dealing with current drug shortages. Send your stories to editor@painnewsnetwork.org.