DEA Missed Deadline for Opioid Production Quotas. Will It Worsen Shortages?

By Pat Anson

In recent years, hundreds of physicians have been prosecuted by the U.S. Justice Department for violations of the Controlled Substances Act (CSA).

In many cases, the doctors were accused of prescribing opioid pain medication without “a legitimate medical purpose” – a vague term in the CSA that was meant to prevent drug abuse, but in practice put the DOJ in charge of deciding whether healthcare decisions involving controlled substances are legal. 

The CSA is rigidly enforced when federal prosecutors believe opioids are prescribed excessively. But when it comes to enforcing another provision in the CSA, the DOJ and Drug Enforcement Administration have routinely ignored deadlines for setting aggregate production quotas (APQs) for opioids and other Schedule I and II controlled substances:

“On or before December 1 of each year, upon application therefor by a registered manufacturer, the Attorney General shall fix a manufacturing quota for the basic classes of controlled substances in schedules I and II.”

The December 1 deadline is important because it gives the pharmaceutical industry a small window to prepare for the coming year by acquiring raw materials for drugs, setting manufacturing schedules, and distributing medications to hospitals and pharmacies – a process that can take as long as six months. . 

But Attorney General Pam Bondi and acting DEA Administrator Terry Cole didn't publish their proposed quotas for 2026 in the Federal Register until November 28, which call for a 6% cut in the supply of oxycodone.

Allowing for a shortened public comment period that ends December 15, and time to review thousands of comments and make changes in the quota allotments, that means the final APQs for next year will likely not be ready until after January 1.

The last time production quotas were that late was in 2024, when the final APQs were not published until January 3. Drug shortages spiked to record levels in the first few months of that year, including many medications that are covered under the quota system. 

Missing the deadline again this year threatens to worsen chronic shortages of oxycodone, hydrocodone, fentanyl, hydromorphone, morphine and amphetamine-based stimulants that are vital to millions of patients who live with pain or attention deficit disorder (ADHD).

The DOJ and DEA did not respond to multiple requests from PNN to explain why the CSA deadline was missed again.

This is not a new problem. Late quotas and drug shortages have persisted for years, as the DOJ and DEA have focused on going after doctors – at times using “flimsy evidence” – rather than ensuring that essential medications are available on time. 

That mindset of being a law enforcement agency first – with maintaining the drug supply an afterthought – may have cost some patients their lives. 

“We talk a lot about opioid misuse, but almost never about the quiet suffering caused when essential pain medicines simply aren't available,” says Lynn Webster, MD, a pain management expert and former president of the American Academy of Pain Medicine. “Chronic delay and rigidity in quota decisions make patients with serious illness feel like collateral damage in a war on drugs that has lost sight of its humanitarian obligations.

“Quotas were meant to curb diversion, not to create a permanent state of scarcity for people in pain. By keeping quotas tight and decisions late, the DEA has turned an already fragile supply chain into a game of musical chairs where patients lose their seats.”

Late Quotas Worsened Drug Shortages

As far back as 2015, the General Accountability Office (GAO) warned in an audit report that the DEA “has not effectively administered the quota process.” Although a decade old, many of the problems cited by the GAO still exist today.

“Each year, manufacturers apply to DEA for quota needed to make their drugs. DEA, however, has not responded to them within the time frames required by its regulations for any year from 2001 through 2014,” the GAO said.

“Manufacturers who reported quota-related shortages cited late quota decisions as causing or exacerbating shortages of their drugs.”

The report found that drugs containing Schedule II controlled substances accounted for over half the shortages between 2001 and 2013. Several manufacturers complained to the FDA the shortages were caused by the DEA’s mishandling of the quota system.

But the DEA denied any responsibility for the shortages, while blaming the missed deadlines on  “inadequate staffing” and an “increasing workload” in its Quota Unit.

“DEA is confident that its administration of the quota process did not affect a shortage during the period of review because drug product shortages are not limited to products that contain Schedule II controlled. substances,” Joseph Rannazzisi, then-DEA Deputy Assistant Administrator, wrote in the agency’s response to the GAO report.

Rannazzisi would later emerge as a “whistleblower” on 60 Minutes, who blamed the opioid crisis on lax policies at the FDA that favored that drug industry.

The relationship between DEA and FDA, at least in 2015, was not one of trust. The FDA advised the DEA about medical demand for Schedule II drugs and any shortages that may exist, but the DEA didn’t always listen.

“DEA and FDA are not able to effectively collaborate due to fundamental disagreement over whether any given shortage exists. DEA has made it clear it does not trust FDA’s information, as it does not consider many of the shortages that FDA verifies to be legitimate,” the GAO said. “They do not believe FDA appropriately validates or investigates the shortages.” 

The GAO concluded that problems in DEA’s Quota Unit run deeper than any petty rivalries with the FDA. 

“Our work shows that DEA’s lack of internal controls, such as controls to ensure data reliability, performance measures, and monitoring of performance, may hinder the agency’s ability to ensure an adequate and uninterrupted supply of controlled substances,” the 2015 report found. “This approach to the management of an important process is untenable and poses a risk to public health.”

New Deadline

The GAO’s critique came at a time when the DEA’s deadline for final APQs was October 1 – a deadline the agency consistently failed to meet. 

To buy itself more time to work on quotas, the DEA lobbied Congress to change the annual deadline to December 1 in the 2018 Support Act, a bill intended to reduce opioid diversion. The DEA also reduced the amount of inventory drug manufacturers are allowed to keep of controlled substances, and agreed to base its quotas on dosages, not the raw supply of drugs.

How has that worked out? Poorly.

The DEA has not only been unable to meet the December 1 deadline, but the smaller inventories have worsened the ability of drug manufacturers to respond to late quotas and emerging drug shortages. 

The pharmaceutical industry warned the DEA that reducing inventories would only worsen shortages and do little to prevent diversion.

“We believe that risks associated with this proposal, including the increased likelihood for drug shortages and market outages, greatly outweigh the negligible benefit this provision will provide,” Larry Cote, an attorney representing a drug manufacturer, wrote to the agency in 2019.

“Given the timing of procurement quota issuance, it will become more imperative to carry increased levels of inventory at year end in order to ensure continued drug supply, as opposed to decreased levels.”

The DEA ignored those warnings and reduced inventories anyway. As a result, analgesic medications needed for surgery and post-op care, such as injectable fentanyl and hydromorphone, have been on the FDA shortage list for years, in part due to low inventories. The two drugs are rarely diverted.

‘Vulnerable to Supply Shocks’

Two pharmacists recently criticized the DEA for its “outdated system” for APQs.

“The current one-size-fits-all system for setting APQs is ineffective and Congress recognized this back in 2018, passing the SUPPORT Act to modernize the APQ setting process and require quota allocations based on dosage form. Yet seven years later, the DEA has failed to implement this law, leaving manufacturers constrained, patients underserved, and the nation vulnerable to supply shocks,” Soumi Saha, PharmD, and Justin Schneider, PharmD, wrote in a recent op/ed published in the Pharmacy Times.   

Saha and Schneider believe many of the quota problems could be addressed if the DEA were to hire a Chief Pharmacy Officer who is familiar with the drug supply system and is put in charge of the quota system.

“It is time to elevate the agency’s clinical responsibility by establishing a Chief Pharmacy Officer (CPO) within the DEA - a role dedicated to ensuring that patient access is not an afterthought, but a core priority,” they said. “A strong CPO would not only modernize quota systems but also bring agility, accountability and patient advocacy to the heart of DEA decision-making.”

To be clear, the DEA is not solely at fault for persistent shortages of opioids and other controlled substances. A 2021 opioid litigation settlement with three drug distributors essentially rationed the supply of opioids at many pharmacies and made pharmacists even more wary of filling new prescriptions. 

In a 2023 PNN survey of over 2,800 patients, 90% said they experienced delays or problems getting their opioid prescriptions filled, mostly because their pharmacy was out of stock. Nearly one in five were unable to get their pain medication, even after contacting multiple pharmacies.

Some generic drug manufacturers have stopped making opioids because of low profit margins and because of concerns they could be targeted by plaintiff law firms in opioid lawsuits that could cost them billions of dollars. 

Bad weather and a heavy reliance on foreign drug manufacturers have also made the supply chain less reliable and contributed to shortages.  

But the DEA’s chronic failure to meet quota deadlines – a problem dating back decades – and its slow-walking of efforts at reforming the quota system, have made a fragile drug supply chain even more vulnerable to disruptions. And it is patients who pay the ultimate price for the DEA’s negligence.

“When DEA repeatedly misses its own deadlines for setting opioid production quotas, that uncertainty reverberates all the way to the bedside,” says Dr. Webster. “Manufacturers pull back, pharmacies ration, and it's the patients – people with cancer, sickle cell disease, or severe chronic pain – who are left wondering if their next prescription will even be filled.” 

Should the DEA hire a Chief Pharmacy Officer? Should deciding what is or isn’t “a legitimate medical purpose” be left to the DEA and DOJ? Only a few days are left to comment on the DEA’s proposed APQs for 2026. You can leave a public comment by clicking here.

Gabapentin’s Side Effects May Lead to ‘Prescribing Cascade’

By Pat Anson

Over the years, we’ve published many warnings about gabapentin (Neurontin), a nerve medication that is widely prescribed off-label for pain conditions it was never intended to treat. 

Common side effects from gabapentin include brain fog, dizziness, weight gain, headache, fatigue, and anxiety. The drug has also been linked to a higher risk of dementia.

According to a new study, those side effects may lead to a “prescribing cascade” in which physicians mistakenly prescribe unnecessary medications to a patient that cause even more side effects. 

The problem is not limited to gabapentin, but includes other gabapentinoids such as pregabalin (Lyrica). Both medications may cause edema – fluid retention and swelling in the legs and feet –  leading doctors to suspect congestive heart failure and prescribe diuretics that can cause kidney injury, light headedness, and falls. 

Researchers with the VA Health Care System and the University of California, San Francisco (UCSF) analyzed the medical records of 120 older veterans, most of whom were male and long-term users of five or more medications. All had taken gabapentinoids and diuretics, which are often prescribed for edema.  

Although none of the veterans had fluid buildup in the year before they started taking gabapentinoids, only 4 doctors suspected the drugs were the culprit and just one discontinued the medication.

The vast majority of physicians – 69 in all – never suspected or downplayed the possibility that gabapentinoids may be causing the edema. Since fluid retention is a symptom of congestive heart failure and poor blood circulation, the veterans were put on loop diuretics such as Lasix.

Within two months, 28 veterans had side effects from the new drugs, including poor kidney function, dizziness, and blurred vision, along with low levels of sodium or potassium, which can disrupt critical body functions. Six patients had symptoms so severe they were hospitalized or taken to an emergency department. 

“Gabapentinoids may be prescribed at unnecessarily high doses or for conditions that they may not help,” said Matthew Growdon, MD, an Assistant Professor of Medicine at UCSF and first author of the study in JAMA Network Open. “In these cases, doctors should consider not prescribing these drugs — or giving lower doses to lessen the risk of prescribing cascades and other side effects.” 

One veteran in his 60’s was put on a heavy dose of gabapentin for neuropathy that was induced by chemotherapy for lung cancer. He developed edema and was switched to pregabalin. When the fluid retention didn’t stop, he was put on a diuretic. Within two days he developed light headedness and felt off-balance, and the diuretic was stopped.

Another patient in his 60’s was prescribed gabapentin twice a day for back pain, an off-label use. After two months he had edema and was put on a diuretic. Soon after, he experienced a fall, went to the ER, and was given IV pain medication. The diuretic and polypharmacy are believed to have contributed to the man falling.

The cases highlight how a prescribing cascade with multiple drugs can have serious health consequences. Patients on gabapentinoids may be prescribed sleep aids, anti-depressants and other medications to counteract the drugs’ many side effects.

Gabapentin is often prescribed off-label for migraine, fibromyalgia, cancer pain, postoperative pain, and many other pain conditions for which it is not FDA-approved. Off-label prescribing is legal and sometimes appropriate, but has reached extreme levels for gabapentin. Studies estimate the drug is prescribed off-label up to 95% of the time. 

“Gabapentinoids are non-opioids, and prescribers associate them with a relatively favorable safety profile,” says senior author Michael Steinman, MD, a Professor of Medicine at UCSF.  “Patients taking them should regularly check in with their doctor to assess whether this is the best treatment for them and consider other options, including non-drug alternatives that might be more appropriate.” 

In 2024, gabapentin was the fifth most prescribed drug in the U.S., with prescriptions nearly tripling since 2010. The number of patients prescribed gabapentin reached 15.5 million in 2024, up from 5.8 million in 2010.

DEA Plans Further Cuts in Oxycodone Supply

By Pat Anson

The Drug Enforcement Administration is planning to cut the supply of oxycodone by over 6% in 2026, along with marginal reductions in the supply of hydrocodone, morphine and other Schedule II opioids. 

If the DEA’s plans are finalized after a short public comment period, it would be the 10th consecutive year the opioid supply has been reduced in the United States.

The DEA announced its plans Friday in the Federal Register. Under the Controlled Substances Act (CSA), the agency has broad legal authority to set annual aggregate production quotas (APQs) for drug makers – in effect telling them the amount of Schedule I and Schedule II chemicals and medications they can produce. 

The DEA is planning another round of cuts in the Schedule II opioid supply because it continues to see declines in the “medical usage” of opioids – an average decrease of 10.5% in 2024 alone. 

It’s important to note that medical usage is different from “medical need.” Doctors simply aren’t prescribing as many opioids as they used to, so while the need for pain relief hasn’t changed and may have even increased due a spike in rates of chronic pain, the number of prescriptions written for opioids has declined. 

DEA expects that trend to continue, based in part on data from IQVIA, a private company that tracks prescription drug use. The agency is also seeing fewer requests from drug manufacturers to make oxycodone.

“DEA projects that the medical usage of these controlled substances will continue to decline in 2026 based on a review of domestic usage data from IQVIA,” DEA said in its Federal Register notice. “Additionally, DEA has observed a significant decline in requests for product development quotas to support manufacturing towards FDA approval of drug products containing oxycodone.” 

DEA Opioid Production Cuts Planned for 2026

• Oxycodone          6.24% decrease

• Morphine             0.559% decrease

• Hydrocodone       0.529% decrease

• Hydromorphone  0.109% decrease

• Fentanyl              0.014% decrease

• Codeine               0.002% decrease

From year-to-year, the cuts may not appear significant. But over the past decade, there has been an historic decline in the nation’s opioid supply. If its current plan is adopted, DEA will have cut the supply of hydrocodone by 72.9% and oxycodone by 70.6% since 2014.

Some of the decline in “medical usage” is driven by scarcity. For example, Endo Pharmaceuticals recently informed the FDA it discontinued production of 2.5, 5, 7.5 and 10 mg Percocet (oxycodone/acetaminophen) tablets. Major Pharmaceuticals stopped making oxycodone/acetaminophen tablets a few months ago. And Teva Pharmaceuticals, a large generic drug maker, stopped making immediate-release oxycodone in 2023.  

The FDA does not currently list oxycodone products on its drug shortage database, but the American Society of Health-System Pharmacists (ASHP) has since 2023. Limited supplies of oxycodone are available from some manufacturers, according to ASHP, while others have the medications on back order.

Hydrocodone/acetaminophen tablets have also been on the ASHP’s shortage list (but not on the FDA’s) since 2023. Major and Camber Pharmaceuticals have both stopped making them.

Health Canada reported a nationwide shortage of oxycodone/acetaminophen combinations over the summer, a shortage that persists today but is expected to resolve soon.

Why would the DEA be reducing production quotas for opioids that are already in short supply?

DEA sets its APQs after consulting with states willing to share their prescription drug data, as well as federal agencies like Health and Human Services and the Food and Drug Administration. 

DEA also asked for input from the Centers for Disease Control and Prevention, an agency in turmoil after several months of layoffs, budget cuts and leadership changes. A response to that request “was inadvertently delayed” at CDC, but DEA says it will take it under consideration when or if it ever arrives. 

“DEA remains committed to monitoring drug shortages, limiting their impact, and resolving them as quickly as possible. DEA continues to seek additional information that will assist in accurately forecasting domestic medical usage and export requirements of schedule I or II substances,” DEA said.

Unlike previous years, when there was a 30-day period for public comments on the DEA’s quota proposal, the agency is only allowing about two weeks. You can leave a comment here, but it must be posted no later than December 15. DEA did not explain why it was reducing the amount of time the public can comment. 

The PAIN GAME: How Pain Medicine Was Criminalized

By Dr. Lynn Webster

“What happened?”

It’s the most basic question you can ask about the opioid crisis. Yet for more than two decades, most of the answers the public has been given have been pre-packaged: Greedy drug companies, corrupt “pill mill” doctors, desperate patients, and a heroic legal system swooping in to clean up the mess.

What almost no one has seen is what was happening inside those prosecutions as they unfolded; in the homes of the accused physicians, in the war rooms of their defense teams, in the quiet panic of the patients who depended on their care.

That’s what makes The PAIN GAME so extraordinary.

More than twenty years ago, filmmaker Erica Modugno Dagher did something journalists almost never do: she embedded herself at the center of an unfolding legal, medical, and political firestorm and started asking, with a genuinely open mind, “What happened?” 

Then she kept the camera rolling for two decades.

Writer and editor Amy Bianco, who now authors The PAIN GAME on Substack, has taken that trove of footage, documents and human stories, and begun unpacking how the legal system — especially the DEA and federal prosecutors — systematically confused pain medicine with crime, and how that confusion still harms patients today.

If you want to understand why doctors are afraid to treat pain, and why patients are still paying the price, I’d urge you to start with Bianco’s first episode. It’s one of the most important stories you’ve never heard.

Targeting Doctors

The origin of The PAIN GAME runs through the work of political scientist Ronald Libby, PhD, whose 2007 book “The Criminalization of Medicine: America’s War on Doctors” documented a wave of prosecutions in which physicians were recast as criminals. 

Instead of tackling the hard work of healthcare reform or rational drug policy, federal and state authorities went after doctors who billed heavily to Medicare and Medicaid, especially those caring for poor and disabled patients with complex pain.

According to Libby, the logic was simple and brutal:

• High billing = “fraud and abuse”

• High opioid prescribing = “drug dealing”

Under that lens, the DEA and U.S. attorneys didn’t need to understand the nuances of chronic pain, palliative care, or Ehlers–Danlos syndrome. They just needed numbers: prescription counts, morphine milligram equivalents, and outlier billing profiles. 

The more a physician’s practice reflected the grim reality of caring for very sick people, the more suspicious they looked on a spreadsheet.

By the early 2000s, news outlets were saturated with stories of “pill mills” flooding communities with OxyContin. Those stories had a ready-made villain and an easy fix: prosecute the doctor, shut down the clinic, and declare victory.

But as The PAIN GAME shows from the inside, it didn’t add up.

A Camera Inside the Crackdown

Because Libby had earned the trust of embattled clinicians, that trust extended to Erica. She was invited into defendants’ homes, their lawyers’ strategy sessions, back-hall conversations at medical and legal conferences, and even the corridors of Congress.

Crucially, she went in without an agenda. There was no narrative she needed to confirm and no “pill mill” caricature she had to deliver. She simply watched and listened as doctors, patients, lawyers, and advocates tried to understand why the government had suddenly turned medicine into a crime scene. That is what makes the series riveting.

Amy’s first episode on Substack tells this origin story from the inside. She weaves in her own path through the pain world, including her friendship with chronic pain advocate Siobhan Reynolds, founder of the Pain Relief Network, and her own diagnosis with Ehlers–Danlos syndrome. She then patiently walks readers through what the footage and documents reveal.

What emerges is not a defense of every prescribing decision ever made. It is something more unsettling: a portrait of a legal system that decided it was easier to dramatize a few high-profile prosecutions than to grapple with the real drivers of overdose and despair.

When the DEA Writes Medical Policy

Once you see these cases from the inside, the larger pattern comes into focus.

Prosecutors leaned on cooperating witnesses, often people who themselves had been charged, to transform complex medical practices into simple crime stories.

DEA agents and auditors treated prescribing volume as guilt, with almost no capacity to distinguish a high-complexity referral practice from a storefront drug operation.

The media, fed a steady diet of press releases and perp walks, amplified the “drug dealers in white coats” narrative until it hardened into common sense.

And while those courtroom dramas played out, something quieter, and more damaging. was happening across the country.

Doctors who were never criminally charged saw colleagues indicted or their offices raided — which led them to decide that continuing to treat high-risk patients simply wasn’t worth taking the chance. 

Pharmacists also grew skittish about filling legitimate prescriptions. Medical boards and hospital systems imposed rigid rules, less in the service of good medicine than to signal compliance and to distance themselves from the crisis that had been miscast in the public eye.  

The overdose crisis surged forward in the meantime, driven increasingly by illicit fentanyl and a volatile street supply that no prosecution could touch. Prescribing plummeted, while overdose deaths soared.

This is the great irony The PAIN GAME helps expose: The very tools we were told would “fix” the crisis — aggressive DEA enforcement against prescribers — did little to curb overdoses. But they have been devastatingly effective at making it harder for people in pain to get care.

Why The Pain Game is Timely Today

You cannot reconstruct this history by looking backward. Many of the key players are gone. The media environment has only grown more hostile toward anyone who challenges the standard narrative about opioids. The raw fear that Libby detected in the early 2000s has turned into a kind of enforced silence.

That’s why Bianco’s work on The PAIN GAME is so valuable. She and Erica were there as it happened. I have learned that they turned over every page in their research: trial transcripts, medical records, internal memos, and obscure legal filings. They followed the story from exam rooms and courtrooms all the way to Capitol Hill, and they never stopped asking, “What actually happened here?”

If you care about pain medicine, civil liberties, or the rule of law, you’ll find The PAIN GAME both captivating and deeply sobering. It shows, in human terms, how we let a criminal justice narrative substitute for real health policy, and how that mistake still shapes the lives of patients and clinicians today.

The first episode is your entry point into that world. Read it. Sit with it. And then, if you find yourself thinking, No one ever told this part of the story, hit the subscribe button on Amy Bianco’s Substack.

We cannot undo the damage that has been done, but we can tell the truth about how it happened. The PAIN GAME is one of the few places where that truth is being documented, carefully and courageously, in real time.

Lynn R. Webster, MD, is a pain and addiction medicine specialist and serves as Executive Vice President of Scientific Affairs at Dr. Vince Clinical Research, where he consults with pharmaceutical companies.

Dr. Webster is the author of the forthcoming book, “Deconstructing Toxic Narratives -- Data, Disparities, and a New Path Forward in the Opioid Crisis,” to be published by Springer Nature.

OTC Pain Relievers Just as Effective as Opioids After Wisdom Tooth Removal

By Pat Anson

A combination of acetaminophen and ibuprofen works just as well as a low dose of opioids in relieving pain in men and women after wisdom tooth removal, according to a new study in JAMA Network Open. 

The research builds on a previous study of over 1,800 patients, which compared the effectiveness of 400 mg of ibuprofen and 500 mg of acetaminophen to 5 mg of hydrocodone and 300 mg of acetaminophen in the first three days after surgery. That dose of hydrocodone is the equivalent of 5 morphine milligram equivalents (MME), which is considered a low dose under medical guidelines.

"We wanted to determine whether the pain medication's effects were consistent in males and females separately," lead author Janine Fredericks Younger, DMD, an associate professor at Rutgers School of Dental Medicine, said in a press release.

 "And what we found is that in both subgroups (males and females), the non-opioid was superior for that first day and night, and then no worse than the opioid for the rest of the post-op period."

Researchers performed a gender-specific analysis because women often report higher pain levels after surgery, raising questions about whether pain medications work differently for each sex.

"There's obviously different biological mechanisms, different hormones involved," said Cecile Feldman, DMD, Dean of Rutgers School of Dental Medicine and senior author of both studies. "But results confirm that the analgesic effect for both groups is the same."

Pain levels were low whether patients took acetaminophen-ibuprofen or the hydrocondone-acetaminophen combination. Pain ratings over three days were slightly lower for female patients taking non-opioids than those on the low dose of hydrocodone (2.83 vs 2.98). The same was true for male patients (2.24 vs 2.37).

Patient satisfaction and sleep quality were also slightly better in the non-opioid group, which also experienced less pain interference with daily activities.

"The results actually came in even stronger than we thought they would," Feldman said. "We expected to find the non-opioid to be non-inferior, so that at least it was no worse than opioids. We were surprised to see that it was actually superior." 

The first FDA-approved over-the-counter pain reliever that combines acetaminophen with ibuprofen was Advil Dual Action, although the doses are somewhat different than what was used in the Rutgers study.

Each capsule contains 250 mg of acetaminophen and 125 mg of ibuprofen, with up to six capsules per day recommended for toothaches, headaches and “minor aches and pain.”

Patients are cautioned not to take Advil Dual Action with other products containing acetaminophen, as that can cause liver damage. Acetaminophen overdoses are involved in hundreds of deaths and over 50,000 emergency room visits in the U.S. annually.

Wisdom tooth extraction is performed about 3.5 million times a year in the United States. Dental surgery is often the first exposure that a patient has to prescription opioids, although their use after dental procedures has declined in recent years as fears grew about opioid addiction.

Last year the American Dental Association (ADA) released new guidelines recommending that nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen be taken alone or in combination with acetaminophen as first-line treatments for acute dental pain in adults and adolescents aged 12 and older. 

NSAIDs and acetaminophen work differently, with NSAIDs reducing pain and inflammation in damaged tissue, while acetaminophen acts in the central nervous system to block pain signals that are not caused by inflammation. Taking the two together is believed to boost their analgesic effect. 

The ADA says opioids should only be used when NSAIDs and acetaminophen don’t relieve pain enough or when NSAIDs are contradicted due to health issues, such as a patient having cardiovascular problems or a bleeding ulcer.     

The risk of long-term opioid use after a tooth extraction is relatively rare. A large study of over 70,000 teens and young adults who had their wisdom teeth removed found that only 1.3% were prescribed opioids long-term after their initial prescription by a dentist. 

"We feel pretty confident in saying that opioids should not be prescribed routinely for dental procedures," Feldman said. "Our non-opioid combination really should be the analgesic choice."

Opioid Prescribing Down Significantly for U.S. Nursing Home Residents

By Pat Anson

Opioid prescribing to U.S. nursing home residents declined significantly over the past decade, the latest sign that efforts to limit access to opioid medication are impacting patients who need them for pain relief.

Researchers at University of California San Francisco (UCSF) looked at health data for nearly 3 million Medicare beneficiaries and found that the likelihood of nursing home residents receiving a prescription opioid fell from 48% in 2011 to 33.5% in 2022. 

The chances of a resident receiving a high daily dose above 50 morphine milligram equivalents (MME) also declined, from 25.1% to 21.9%. 

Over half of nursing home residents have chronic pain from arthritis, osteoporosis, degenerative disc disease and other age-related conditions. The average age of residents in this study was 84.

“We weren’t expecting to see a decline, especially for people who are actually reporting high incidence of chronic pain,” first author Ulrike Muench, an associate professor at UCSF School of Nursing, told the San Francisco Chronicle. “It might be a good thing that opioids are used less, but at the same time it raises concerns about potentially untreated pain for individuals who are in need of pain medications.”

The study is believed to be the first to examine opioid prescribing to nursing home residents after the release of the CDC’s 2016 opioid guideline. Although that voluntary guideline was intended only for patients being treated for chronic pain by primary care providers, it essentially became the default guideline for all patients and doctors of every specialty.

Opioid prescriptions to nursing home residents were falling even before the CDC guideline was released, with the decline affecting every racial and ethnic group. 

Opioid Prescribing to U.S. Nursing Home Residents

JAMA INTERNAL MEDICINE

“These reductions parallel national patterns in primary care and may reflect implications of opioid-related policies, such as the 2016 Guideline, extending beyond their intended setting. Some residents may have benefitted from opioid reductions, but others may face barriers to adequate pain control,” researchers reported in JAMA Internal Medicine.    

“We also observed that minoritized residents were consistently less likely to receive opioids and higher daily MMEs, suggesting that prescribing decisions may not be based solely on clinical need.”

White nursing home residents were significantly more likely to be prescribed an opioid for pain than residents who are Black, Hispanic, Asian or Native American, even though minority residents are more likely to have severe pain.   

Previous studies have also documented declines in opioid prescribing to cancer patients, as well as seriously ill patients in palliative or hospice care  – groups that were supposed to be exempt from the CDC guideline.

Rx Opioids Are Not a Cure… and Neither Is Anything Else

By Neen Monty

They deliver it like it’s some kind of mic drop.

“Opioids are not a cure,” they say.

But here’s the important thing: Almost nothing in medicine is a cure.

Insulin doesn’t cure diabetes. But it keeps people alive.

Methotrexate and Xeljanz don’t cure rheumatoid arthritis. They slow down disease progression though.

Intravenous immunoglobulin is not a cure for Chronic Inflammatory Demyelinating Polyneuropathy. But it slows down the demyelination of my nerves.

Prednisone is not a cure for autoimmune disease. But it reduces inflammation, which improves pain and quality of life.

Anti-inflammatories do not cure inflammatory arthritis, but they decrease pain, increase function and improve quality of life.

Metformin, thyroxine, even chemotherapy in many cases… none are cures.

They manage symptoms, reduce harm, and improve quality of life.

That’s medicine’s job.

Medicine is not purely about curing disease. In fact, it’s rarely about curing disease. That does not mean that all the wonderful things that medicine can do are worthless.

So why is pain relief held to a higher standard than every other kind of treatment?

Why are opioids dismissed simply because they don’t cure the underlying disease that causes the pain?

Pain relief is not a moral failing. It’s medicine doing what it’s meant to do: Alleviate suffering and restore function.

That’s what opioids do. Alleviate suffering, restore function and improve quality of life. Those are good things.

If you can move again, sleep again, think clearly again, participate in life again, isn’t that a good thing?

But no. Dismiss opioids because they’re not a cure.

Such a stupid point of view.

Now that we’ve shown that chronic pain patients hardly ever become addicted or overdose on their pain medication, people are really reaching for reasons to demonize opioids. Saying that opioids are not a cure is reaching pretty hard.

Opioids reduce pain temporarily. I am under no illusions. And I do wish there was a cure for my diseases. I really do. But there is no cure. There is only palliative treatment -- with opioids.

And so many people would like to take that pain relief away from me. People who have never experienced severe pain at 1am. So severe that sleep is impossible. So constant that it happens every night. And all day, every day.

Except for the few hours when I have pain medication to reduce that pain – while not curing it.

Opioids don’t cure pain any more than insulin cures diabetes. They treat a symptom. A devastating symptom – severe pain - that profoundly affects function and quality of life.

Reducing that pain, even temporarily, is not a failure.

That’s a treatment working.

It’s the best treatment we’ve got for severe pain, acute or chronic.

To say “opioids are not a cure” is to fundamentally misunderstand what they’re for.

You know, those glasses you wear won’t cure your shortsightedness. Let’s take your glasses away. They’re not a cure!

That wheelchair won’t cure paralysis. You don’t need a wheelchair.

We don’t apply this logic to any other condition or treatment. Only pain. Only opioids.

We don’t tell people with heart failure to throw away their meds because they don’t “fix” the heart.

We don’t tell people with asthma to stop their inhalers because they don’t “cure” the lungs.

We treat to relieve symptoms, to restore life and dignity, because that’s the ethical duty of medicine.

Relief of suffering is an outcome. Improved function is an outcome. But a cure is wishful thinking.

So the next time someone says, “Opioids are not a cure,” remember that neither is anything else we use to keep people alive, moving, and human.

And that’s okay. Because that’s the best we can do, in many situations.

Because the goal of medicine isn’t always to cure. It’s to care.

Neen Monty is a patient advocate in Australia who lives with rheumatoid arthritis and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), a progressive neurological disease that attacks the nerves.

Neen is dedicated to challenging misinformation and promoting access to safe, effective pain relief. She has created a website for Pain Patient Advocacy Australia to show that prescription opioids can be safe and effective, even when taken long term. You can subscribe to Neen’s free newsletter on Substack, “Arthritic Chick on Chronic Pain.”

Eli Lilly Abandons Another Experimental Non-Opioid Pain Reliever

By Crystal Lindell

Eli Lilly's experimental non-opioid pain medication – named LY3857210 – had lackluster results in clinical trials, the latest setback for Big Pharma in developing alternatives to opioid analgesics.  

The pharmaceutical company told Fierce Biotech that the oral medication, which is a P2X7 inhibitor, "did not meet our high internal bar for success and is being removed from the pipeline for pain."

P2X7 inhibitors are being studied for their potential to relieve chronic pain and cancer-related pain by inhibiting inflammation and nerve signaling. 

But when Lilly tested LY3857210 in Phase 2 trials on patients with osteoarthritis and diabetic neuropathic pain, it performed no better than a placebo in relieving pain. 

The company originally purchased licensing for the drug from Asahi Kasei Pharma in 2021 for $20 million. The Japanese pharmaceutical company had already put the drug through Phase 1 testing when Eli Lilly stepped in.

Although it did not prove to be helpful for pain, Lilly said they were still exploring other uses for it.

In August of this year, Lilly also halted development of mazisotine, another non-opioid pain medication it was developing. Mazisotine blocks pain signals in peripheral nerves, but also had disappointing results in Phase 2 trials.

Lilly is still focused on finding non-opioid pain treatments. In May of this year, the company acquired SiteOne Therapeutics in a deal worth as much as $1 billion. At the time, SiteOne said it was “dedicated to the development of safe and effective pain therapeutics without the significant addiction potential and side effects of opioids.”

SiteOne had been working on a new class of non-opioid medications that target sodium channels in the peripheral nervous system to treat pain and other nerve conditions. Blocking pain signals in peripheral nerves before they reach the brain means the drug theoretically is less likely to lead to addiction or overdoses.

But that approach to pain relief has had mixed results. In August, Vertex Pharmaceuticals halted development of a drug called VX-993 after disappointing results in clinical trials.VX-993 is another non-opioid that blocks pain signals in peripheral nerves, but when given to patients recovering from bunionectomy surgery, it was only slightly more effective than a placebo.

VX-993 is similar to Journavx (suzetrigine), a non-opioid developed by Vertex that also works on peripheral nerves. Journavx was approved by the FDA in January to treat moderate to severe acute pain, despite results in clinical trials that showed it was no more effective than Vicodin.

Tramadol Revisited: Some Patients Say It Helps Relieve Pain

By Pat Anson

A recent study that found tramadol was only slightly effective in relieving chronic pain – but not worth the side effects – is stirring some debate.

The Danish study analyzed findings from 19 clinical trials of tramadol involving over 6,500 patients, and found that the synthetic opioid was not only ineffective for many patients, it may raise the risk of heart disease and perhaps even cancer.

“The potential harms associated with tramadol use for pain management likely outweigh its limited benefits,” researchers reported in the journal BMJ Evidence Based Medicine.

That conclusion is being disputed by John Bumpus, PhD, a Professor of Chemistry and Biochemistry at the University of Northern Iowa.

“In my view, the authors’ analysis and evidence base are far too sparse and fragile to justify the conclusion that harms likely outweigh benefits. Their claims appear overstated and are not supported by the biomedical literature and the underlying data,” Bumpus told PNN.

Bumpus reviewed several studies on his own, including one that found a high dose of tramadol provided “good” pain relief to 74% of cancer patients. The same study found tramadol “satisfactory” for 10% of cancer patients and “inadequate” for about 16% of them.

That wide variability in response, according to Bumpus, is likely due to the individual metabolism of each patient. The effectiveness of tramadol depends on whether they have variations in a gene (CYP2D6) that helps convert tramadol to a metabolite that binds to mu opioid receptors in the brain, resulting in pain relief. 

Another study estimated that 0.5–6.5% of patients are “poor metabolizers” of tramadol, 10–44% are “intermediate metabolizers” and only 43–67% are “normal metabolizers.” Poor and intermediate metabolizers are likely to experience little pain relief from tramadol.

‘It’s the Only Thing That’s Working’

Over the years, many PNN readers have told us tramadol didn’t give them any pain relief. But some say it works for a wide variety of pain conditions.

“I am one who receives adequate pain relief from tramadol. It's all I took, besides ibuprofen, when my pain was being treated, and it was especially effective if I took half a dose on top of regular dose of ibuprofen. After surgery, I took a whole dose of tramadol as prescribed, with adequate pain relief,” one reader said.

“I have autoimmune arthritis and take tramadol so that I can numb the pain to be able to sleep,” another reader wrote.

“It’s the only thing that’s working for my pain. Hydrocodone didn’t even touch it. Oxycodone works only if I add tramadol,” another pain patient told us.

“It does help cut the pain down for me quite a bit. Does it take it all away? No it does not. And some types of pain it doesn’t even touch,” said a woman with arthritis, fibromyalgia and degenerative disc disease. “My sleep has improved quite a bit also since being back on it. But you have to keep it in your system for it to help. You can’t really take it just whenever.”

“It most definitely takes the edge off of my peripheral neuropathy. I have a neurostimulator implant too, but by the end of the day my pain is worse and that’s when I take tramadol,” another patient wrote.

If tramadol is only effective in about half of patients, should it be used at all? Bumpus says it should. Just because tramadol is a “weaker” opioid doesn’t make worthless.

“Tramadol’s analgesic potency is approximately one-tenth that of morphine. Interestingly, this is one reason it is often prescribed first, consistent with the principle of using the lowest effective opioid dose,” Bumpus said.

“For patients whose pain is not adequately controlled, stronger opioids (e.g., oxycodone, hydrocodone) or combination agents (e.g., acetaminophen/oxycodone 325/5 mg) may be appropriate. Thus, for patients who do not respond to tramadol, the remedy is straightforward. They should consult their healthcare provider and consider another medication or alternative therapy.”

That may not be an option for some patients, who have doctors that are only willing to prescribed tramadol and other less risky opioids. The DEA classifies tramadol as a Schedule IV controlled substance in the United States, meaning it has “a low potential for abuse.” Oxycodone and hydrocodone, on the other hand, are Schedule II drugs, meaning they have a “high potential for abuse.”

Bumpus also disputes the notion that tramadol raises the risk of heart problems, pointing out that coronary heart disease (0.45%) and chest pain (0.32%) occurred in less than one percent of patients on tramadol, which is not considered a statistically significant risk.

“The claim… that tramadol’s potential harms outweigh its benefits is not supported by the numerical data presented. Across thirteen clinical trials, tramadol was consistently found to be an effective and generally safe analgesic for chronic pain,” Bumpus said. “Taken together, the available evidence supports tramadol as a reasonable option for appropriately selected patients, provided it is used with good clinical judgment and proper monitoring.”

Although tramadol is the only opioid that some doctors will prescribe for pain, its use is actually declining in the United States. In 2023, over 16 million prescriptions were written for tramadol, down from 25 million a decade earlier.

Opioid Prescribing Falls in Canada, But Are Patients Better Off?

By Pat Anson

The number of patients prescribed opioids for pain in Canada has fallen over 11% in recent years, according to a new study published in the Canadian Medical Association Journal (CMAJ). The decline reflects trends in the U.S. and other Western nations, which adopted stronger guidelines to discourage opioid prescribing nearly a decade ago.

Like most studies of its kind, the new research only looked at the number of opioid prescriptions that were dispensed, and did not evaluate the health or quality of life of Canadian patients after access to opioids was reduced, or whether their pain improved using non-opioid pain therapies.

In 2022, about 1.8 million Canadians began taking an opioid to manage pain for the first time, 8% less than when the study period began in 2018.

“Our study provides valuable information on the progressive decline of prescription opioid dispensing for pain and high-dose initiations among new users, as well as the types of opioids prescribed and important geographic differences in these trends across Canada,” wrote lead author Nevena Rebić, PhD, a clinical researcher at Unity Health Toronto.

“Our findings suggest that national efforts to promote opioid stewardship and safer opioid prescribing for acute and chronic noncancer pain over the past decade have had an impact.”

“High-dose initiations” were defined as daily dosages that are above Canada’s recommended dose of 50 morphine milligram equivalents (MME) or lower. Less than 20% of new prescriptions in Canada exceeded 50 MME. Over half of the opioid prescriptions were for codeine.

Patients most likely to be prescribed an opioid were females, older adults, rural residents, and those living in lower-income areas.

Manitoba consistently had the highest rate of opioid prescribing, while British Columbia had the lowest among the six provinces that were studied. The lower rate in BC is somewhat surprising, given the province’s reputation as the being the epicenter of the “opioid crisis” in Canada.

Monthly Rate of Opioid Prescribing in 6 Canadian Provinces

SOURCE: CMAJ

Rebić and her colleagues cautioned that “ongoing monitoring is needed” to ensure that pain patients are not left suffering from inadequate pain management, rapid opioid tapering or discontinuation, or that they turn to street drugs for relief. The authors acknowledge that has occurred “in some cases,” without exploring the severity of the problem.

“If the (opioid) pain prescribing is better, then why do we still get letters from patients in extreme pain telling us they were cut off, tapered or refused medical care?” asks Marvin Ross of the Chronic Pain Association of Canada (CPAC), which has long criticized Health Canada and the authors of Canada’s medical guidelines for discouraging the use of opioids.

Ross said the new analysis of opioid prescriptions was “a waste of time, money and effort,” and called the researchers “inane pill counters” who lack clinical experience with patients.

“The purpose of prescribing a pill is to help the patient get better or to ameliorate their symptoms, so saying we prescribed 10% fewer pills tells you nothing about that. To focus on the number says nothing about achieving prescribing goals unless you begin from the bias that prescribing any of it is bad,” Ross told PNN in an email. 

In a commentary on the study also published in CMAJ, an anti-opioid activist claimed that addiction and other potential harms of opioids are being overlooked by Canadian doctors who still prescribe them too freely.

“Most clinicians have seen first-hand how well opioids can work when first given. But they are at their pharmacologic best in the initial days of treatment. Continue them for weeks, months, or years and the calculus becomes progressively less favourable,” wrote David Juurlink, MD, a clinical internist at Sunnybrook Research Institute, and a member of Physicians for Responsible Opioid Prescribing (PROP).

“In this way, opioids transition from effective analgesics to drugs required primarily to stave off a withdrawal syndrome they themselves created.”

According to a recent analysis by Health Canada, only 18% of fatal opioid overdoses in Canada in early 2025 involved a pharmaceutical opioid. The vast majority of deaths were linked to illicit fentanyl, fentanyl analogues, and other illicit opioids such as heroin.

Ketamine Infusions Safe and Effective in Treating Chronic Pain

By Pat Anson

There are many pros and cons about the therapeutic effects of ketamine. When misused, the anesthetic drug can lead to tragedy – such as the accidental drowning death of actor Matthew Perry. And although ketamine is increasingly used to treat depression and other psychiatric disorders, the FDA “has not determined that ketamine is safe and effective for such uses.”  

Even ketamine’s use as a pain reliever has been challenged, with a recent study finding “a lot of uncertainty” about its effectiveness in treating difficult chronic pain conditions such as Complex Regional Pain Syndrome (CRPS). The authors of that study said they could find “no convincing evidence” that ketamine delivered meaningful benefits to people in pain.

A new study at the Cleveland Clinic debunks many of those findings. After following over 1,000 pain patients who received ketamine infusions, researchers concluded the infusions are safe and effective for people with chronic pain.

“We know millions of Americans are suffering from chronic pain and this research addresses critical gaps in pain management and shows a significant step forward in improving care for those patients who have otherwise exhausted all other treatment options,” said co-author Pavan Tankha, DO, medical director of Comprehensive Pain Recovery in the Cleveland Clinic’s Neurological Institute.

“The findings of the research represent a meaningful step toward improved quality of life and may accelerate access to this treatment option for patients all over the country.”

Tankha and his colleagues focused on outpatients who received low dose ketamine infusions – 0.5 mg/kg over 40 minutes for five consecutive days. Their findings, recently published in the journal Regional Anesthesia & Pain Medicine, show that over 90% of patients completed all five treatment days, demonstrating the feasibility of outpatient infusions.

Although pain relief in most patients “did not reach clinically meaningful thresholds,” up to 46% reported improvements in their pain, daily functioning, sleep, anxiety, depression, fatigue and quality of life. The improvements were sustained over 3 and 6-month follow up periods, with 80% of patients returning for additional infusions, a telling sign the treatment has benefits.

The research also demonstrated that low-dose ketamine has minimal side effects. Hallucinations, the most common side effect, were rare. No serious adverse events were reported by any patients.

“This study provides evidence for ketamine's role in chronic pain management,” said co-author Hallie Tankha, PhD, a clinical pain psychologist in the Cleveland Clinic’s Primary Care Institute.

“This is in line with my clinical experience as a pain psychologist, as patients often describe ketamine infusions as ‘life changing.' I'm encouraged by treatments that can be integrated into comprehensive care approaches, and this study demonstrates ketamine can be safely and effectively implemented in pain management settings.”

Researchers say their findings demonstrate that ketamine infusions can be part of a pain management program, when combined with behavioral therapies and patient education. The findings also give hope to millions of pain sufferers with complex conditions that have not responded to conventional treatment.

“Given the limited evidence for ketamine infusion protocols in chronic pain and existing access barriers, these real-world findings may help inform patients, payers, and healthcare systems about the potential of standardized KIT (ketamine infusion therapy),” researchers concluded.  “Our findings support integration into multidisciplinary pain centers and lay the groundwork for generating evidence needed for policy and coverage decisions.”

Although the FDA has not approved the use of ketamine in treating pain, some professional medical organizations have for certain conditions. The American Society of Anesthesiologists, American Society of Regional Anesthesia and Pain Medicine, and the American Academy of Pain Medicine have guidelines that support ketamine infusions for CRPS, chronic neuropathic pain and short-term acute pain. 

Study Finds Tramadol Not That Effective for Chronic Pain

By Pat Anson

One of the most widely prescribed opioid painkillers in the world is not that effective at relieving chronic pain and increases the risk of serious side effects such as heart disease, according to a new study.

Tramadol is a synthetic opioid used to treat moderate to severe pain. It is widely perceived as a weaker and “safer” opioid, but the new research found otherwise.

“Tramadol may have a slight effect on reducing chronic pain, while likely increasing the risk of both serious and non-serious adverse events,” wrote lead author Jehad Barakji, MD, a researcher at the Copenhagen Trial Unit at the Centre for Clinical Intervention Research in Denmark.

“The potential harms associated with tramadol use for pain management likely outweigh its limited benefits.”

Barakji and his colleagues analyzed findings from 19 clinical trials of tramadol involving over 6,500 pain patients, making it the first study to assess tramadol’s efficacy and safety across a range of chronic pain conditions.

Five of the studies looked at the impact of tramadol on neuropathic pain; nine focused on osteoarthritis; four looked at chronic lower back pain; and one focused on fibromyalgia.

The findings, published in BMJ Evidence Based Medicine, show that while tramadol eased pain, the effect was small and below what would be considered clinically effective. Tramadol also appeared to increase the risk of cardiac events, such as chest pain, coronary artery disease, and congestive heart failure. 

Use of tramadol was also associated with a higher risk of neoplasms, an excessive growth of tissue that could be an early sign of cancer. However, researchers say the evidence of a tramadol-cancer connection was “questionable” because the studies analyzed were not long enough.

Non-serious side effects caused by tramadol include nausea, dizziness, constipation and somnolence.

Tramadol is considered a weak opioid because it does not bind directly to opioid receptors in the brain like other opioids do. Many patients say tramadol gives them little or no pain relief, but it’s often the only opioid their doctor is willing to prescribe.

In 2023, over 16 million prescriptions were written for tramadol in the United States, down from 25 million prescriptions a decade earlier. Tramadol is classified as a Schedule IV controlled substance in the U.S., indicating it has a low potential for abuse and addiction compared to other opioids.

The consumer watchdog group Public Citizen unsuccessfully petitioned the FDA and DEA in 2019 to upschedule tramadol to a more restrictive Schedule II substance, saying tramadol was “an increasingly overprescribed, addictive, potentially deadly narcotic.”

Tramadol is widely abused by youths in Asia and Africa, where it is often mixed with soft drinks, energy drinks and alcohol to induce euphoria.

What You Should Know About Tylenol and Autism

By Mark Louie Ramos

Claims from the Trump White House about links between use of the painkiller acetaminophen – often sold under the brand name Tylenol in the U.S. – during pregnancy and development of autism have set off a deluge of responses across the medical, scientific and public health communities.

As a father of a child with level 2 autism – meaning autism that requires substantial support – and a statistician who works with such tools as those used in the association studies cited by the White House, I find it useful to think about the nuances of association versus causation in observational studies. I hope that this explanation is helpful to parents and expecting parents who, like me, are deeply invested in the well-being of their children.

Association Is Not Causation, But…

Most people have heard this before, but it bears repeating: Association does not imply causation.

An often-cited example is that there is a very strong association between ice cream sales and incidents of shark attacks. Of course, it goes without saying that shark attacks aren’t caused by ice cream sales. Rather, in the summertime, hot weather drives more appetite for ice cream and beach time. The increased number of people at the beach does, in turn, cause the likelihood of shark attacks to increase.

Yet pointing this out on its own is neither intellectually satisfying nor emotionally appeasing when it comes to real-life medical concerns, since an association does suggest potential for a causal relationship.

In other words, some associations do end up being convincingly causal. In fact, some of the most consequential discoveries of the past century in public health, like the links between smoking and lung cancer or the human papillomavirus (HPV) and cervical cancer, started out as findings of very strong association.

So when it comes to the issue of prenatal acetaminophen use and autism development, it is important to consider how strong the association found is, as well as the extent to which such an association could be considered causal.

Establishing Causal Association

So how do scientists determine if an observed association is actually causal?

The gold standard for doing so is conducting what are called randomized, controlled experiments. In these studies, participants are randomly assigned to receive treatment or not, and the environment where they are observed is controlled so that the only external element that differs among participants is whether they received treatment or not.

In doing this, researchers reasonably ensure that any difference in the outcomes of the participants can be directly attributed as being caused by whether they received the treatment. That is, any association between treatment and outcome can be considered causal.

Yet oftentimes, conducting such an experiment is impossible, unethical or both. For instance, it would be highly difficult to gather a cohort of pregnant women for an experiment and extremely unethical to randomly assign half of them to take acetaminophen, or any other medication for no particular reason, and the other half not to.

So when experiments are simply infeasible, an alternative is to make some reasonable assumptions on how observational data would behave if the association was causal and then see if the data aligns with these causal assumptions. This can very broadly be referred to as observational causal inference.

Parsing What the Studies Mean

So how does this apply to the current controversy over the potential for acetaminophen use during pregnancy to affect the fetus in a way that could result in a condition like autism?

Researchers who try to understand causal roles and links between one variable and potential health outcomes do so by considering: 1) the size and consistency of the association across multiple attempts to estimate it, and 2) the extent to which such association has been established under observational causal inference frameworks.

As early as 1987, researchers have been working to measure possible associations between acetaminophen use during pregnancy and autism. A number of these studies, including multiple large systematic reviews, have found evidence of such associations.

For instance, a 2025 review of 46 studies that examined association between acetaminophen use and an array of neurodevelopmental disorders, including autism, identified papers with five positive associations between acetaminophen and autism.

In one of those studies, which examined 73,881 births, the researchers found that children who were exposed to acetaminophen prenatally were 20% more likely to develop borderline or clinical autism spectrum conditions. Another examined 2.48 million births and reported an estimated association of only 5%.

Both of those are weak associations. For context, estimations of increased lung cancer risk from smoking in the 1950s were between 900% to 1,900%. That is, a smoker is 10 to 20 times more likely than a nonsmoker to develop lung cancer. By comparison, in the two autism studies above, a pregnant woman who takes acetaminophen is 1.05 to 1.20 times more likely than one who does not take the drug to have a child who would be later diagnosed with autism.

Not All Studies Are Created Equal

It’s also important to keep in mind that many factors can affect how well a study is able to estimate an association. In general, larger sample sizes provide both greater power to detect an association if one does exist, as well as improved precision over estimating the value of the association.

This does not mean that studies with smaller sample sizes are not valid, only that from a statistical perspective, researchers like me place greater confidence in an association drawn from a larger sample size.

Once an association – even a small one – is established, researchers then must consider the extent to which causation can be claimed. One way to do this is through what’s called dose-response. This means looking at whether the association is higher among women who took higher doses of acetaminophen during pregnancy.

The study mentioned above that looked at 2.48 million births shows an example of dose-response. It found that pregnant women who reported taking higher doses have higher autism risk.

Another way to examine possible causality in this context is to analyze sibling outcomes, which that same paper did. Researchers looked at whether associations between acetaminophen and autism persisted within families with more than one child.

For example, in a family with two children, if the mother used acetaminophen during one pregnancy and that child was later diagnosed with autism, but she did not use it during the other pregnancy and that child was not diagnosed, then this strengthens the causal claim.

Conversely, if acetaminophen was used during the pregnancy of the child who was not diagnosed with autism and not used during the pregnancy of the child who was, then that weakens the causal claim. When this was included in the analysis, the dose-response disappeared, and in fact the overall 5% increased risk mentioned before likewise disappeared. This weakens the claim of a causal relationship.

At present, there is clearly not enough evidence to establish a causal association between prenatal acetaminophen use and autism.

Yet as a parent who wonders if my daughter will ever be able to write her name, or hold a job or raise kids of her own, I understand that such explanations may not appease the fears or concerns of an expecting mother who is suffering from a fever.

Naturally, all of us want absolute certainty. But that’s not possible when it comes to acetaminophen use, at least not at this time.

Your doctor will be able to provide you with much sounder advice than any existing study on this topic. Your OB-GYNs are very likely aware of these studies and have much better judgment as to how these results should be considered in the context of your personal medical history and needs.

Researchers, meanwhile, will continue to dig deeper into the science of this critically important issue and, hopefully, provide greater clarity in the years to come.

Mark Louie Ramos, PhD, is an Assistant Research Professor of Health Policy and Administration at The Pennsylvania State University.

His research experience includes statistical development and multidisciplinary projects involving large datasets such as the United Kingdom Biobank, the National Health and Nutrition Examination Survey, and the United States Military Health System. He has taught mathematics and statistics subjects for over 20 years.

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

Over 15 Million Americans Prescribed Gabapentin Despite Warnings

By Pat Anson

The use of gabapentin (Neurontin) continues to soar in the United State, often for chronic pain and other health conditions the drug is not approved to treat, according to a new analysis by CDC researchers.

In 2024, gabapentin was the fifth most prescribed drug in the U.S., with prescriptions nearly tripling since 2010, according to findings published in the Annals of Internal Medicine. The number of patients prescribed gabapentin reached 15.5 million in 2024, up from 5.8 million in 2010.

Gabapentin was originally developed as an anti-convulsant. It was first approved by the FDA as a treatment for epilepsy and later for neuropathic pain caused by shingles. But it is also routinely prescribed off-label for depression, ADHD, migraine, fibromyalgia, bipolar disorder, cancer pain, postoperative pain, and many other conditions.

Off-label prescribing is legal and, in some cases, appropriate. But for gabapentin it has reached extreme levels, with studies estimating the drug is prescribed off-label up to 95% of the time. Gabapentin has been used to treat so many different health conditions that a drug company executive called it “snake oil.”

"This study highlights a slowed, but continued, increase in gabapentin dispensing from retail pharmacies in the United States," wrote lead author Gery Guy Jr., PhD, of the CDC National Center for Injury Prevention and Control. "As gabapentin dispensing continues to increase, particularly among older populations, prescribing physicians and advanced practitioners should be alert to the potential adverse effects of gabapentin."

Side effects from gabapentin include mood swings, depression, dizziness, fatigue and drowsiness.  A recent study found that gabapentin raises the risk of dementia.

Gabapentin has also become a street drug, after drug users found it can heighten the effects of heroin, cocaine and other illicit substances. Nearly 10% of overdose deaths in 2020 involved gabapentin, with most of those deaths also involving illicit opioids. A recent analysis of drug tests found gabapentin in over 13% of urine samples that tested positive for fentanyl.

“Although gabapentin alone is infrequently involved in fatal overdose, serious breathing difficulties may occur in patients with respiratory conditions or those using gabapentin in combination with opioids,” said Guy.

The CDC has a checkered history with gabapentin. The agency’s 2016 opioid prescribing guideline promoted gabapentin and its sister drug pregabalin as non-opioid alternatives for neuropathic pain, without any mention of their possible side effects.

The CDC’s revised 2022 opioid guideline is a bit more cautious. It says gabapentin can produce “small to moderate improvements in chronic pain and function,” but can also cause blurred vision, cognitive effects, sedation, and weight gain.

Medical experts say doctors need to do a better job warning patients about the side effects of gabapentin, and the medication should be stopped if a patient reports little or no benefit. They also think medical guidelines have exaggerated the effectiveness of gabapentin and should be revised.

How Opiophobia Paved the Way for Tylenol Hysteria

By Crystal Lindell

The dirty little secret about alternatives to opioids is that they are all mostly bullshit.

They’re expensive, sometimes outright dangerous, and perhaps worst of all, ineffective.

So when doctors are telling you that you don’t need opioids to treat your pain, what they are really saying is that you don’t need pain treatment at all.

And that’s exactly the message that people are getting from the Trump administration’s recent guidance to avoid taking Tylenol while pregnant.

Specifically, the administration is now advising women not to use acetaminophen — which goes by the brand name Tylenol — for pain and fever during pregnancy due to claims that it raises the risk of their babies developing autism. 

Aside from the fact that science behind this claim is not definitive, the other major problem is that there is no safe alternative to acetaminophen that a woman can take for pain and fever while pregnant. Over-the-counter pain relievers like aspirin and ibuprofen can damage the kidneys of unborn babies.

President Trump admitted as much during the press conference about the new guidance, putting the onus on pregnant women to “tough it out” by not taking Tylenol

“Sadly, first question, what can you take instead? It's actually, there's not an alternative to that,” Trump said. “And as you know, other medicines are absolutely proven bad. I mean, they've been proven bad, the aspirins and the Advils and others, right?

“But if you can't tough it out, if you can't do it, that's what you're going to have to do. You'll take a Tylenol, but it'll be very sparingly.”

That’s a genuinely inhumane response to the pain pregnant women often endure, because what he’s really saying is that you just should not treat pain while pregnant. It’s also on-brand messaging for an opiophobic country that’s been dismissing everyone’s pain for almost a decade now.

As it turns out, when you tell people that their pain doesn’t deserve to be treated by opioids, then it’s a quick path to the idea that pain shouldn’t be treated by other substances, be they cannabis or kratom or Tylenol. 

In the end, it all really comes down to a fundamental question of whether or not pain is worthy of treatment.

And unfortunately, for many healthcare professionals and government officials, the answer is a resounding “no.” They do not believe that pain is worthy of treatment – as long as it’s not their pain. Because, make no mistake, when these types of policies come out, that’s exactly who they apply to: other people.

They know that they themselves will get to use opioids if and when the time comes that they need them for their own pain. And they don’t expect to have a pregnancy themselves, so of course they don’t care if pregnant women can’t have their pain treated.

It's why Trump can so dismissively say "there's no downside in not taking it." He means there is no downside to him if you don’t take Tylenol.

But for pregnant women, there most certainly is a downside. Failing to treat fever and significant pain can pose serious risks to both the mother and baby, resulting in miscarriages, birth defects, depression, infections and high blood pressure.

Enduring untreated pain can wear you down in ways you can’t even predict. It will destroy your sleep, steal your hope, and even make you mean. When it’s your pain, you’ll do anything to make it stop.

Pain is a medical condition on its own, and “toughing it out” is not an effective treatment. Until we as patients and voters demand better, I fear both the government and our healthcare system will continue chipping away at the pain treatments we still have — until there is literally nothing left but silent prayers and fleeting wishes.