Is JAMA Opioid Study Based on Junk Science?

By Pat Anson, Editor

You may have read about a research study published this week in the Journal of the American Medical Association (JAMA), which compared the effectiveness of opioid and non-opioid medications in treating chronic pain. 

The yearlong study of 240 patients found that opioids were not superior to pain relievers like acetaminophen and ibuprofen in treating chronic back pain or hip and knee pain caused by osteoarthritis.  Pain improved for 41% of the patients who took opioids, compared to 54% in the non-opioid group.  

It’s an interesting study – one of the few to look at the effectiveness of any pain relievers long term – but some critics are questioning the study’s methodology and the alleged anti-opioid bias of its lead author, Erin Krebs, MD, a researcher for the Department of Veterans Affairs.

First let’s look at some of the news coverage the study is getting.

“Opioids Don’t Treat Chronic Pain Any Better Than Ibuprofen” reads the headline in Newsweek, an article that never mentions the JAMA study was limited to patients with back pain or osteoarthritis.

“Opioids Don’t Beat Other Medications for Chronic Pain” was the headline in, while the Chicago Tribune went with “Opioids no better than common painkillers for treating chronic pain.”

The Tribune article included a quote from one of the co-authors of the CDC opioid guidelines. "The fact that opioids did worse is really pretty astounding," said Roger Chou, MD. "It calls into question our beliefs about the benefits of opioids."


Notice the news coverage strongly suggests that opioids are ineffective for all types of chronic pain – not just back pain and osteoarthritis.  Patients living with chronic pain from arachnoiditis, trigeminal neuralgia or some other intractable pain condition would probably disagree about that. And they'd find the idea of taking ibuprofen laughable, if not infuriating. But no one asked for their opinion.

Also unmentioned is that opioids are usually not prescribed for osteoarthritis or simple back pain, which are often treated with NSAIDs and over-the-counter pain relievers.

So, what JAMA has published is a government funded study designed to look at a treatment (opioids) that most people with back pain and arthritis never actually get.

“You've been had by anti-opioid advocates disguising their advocacy as science.  Krebs is well known in professional circles for this kind of distorted advocacy junk science,” wrote patient advocate Red Lawhern, PhD, in a comment submitted to the Philadelphia Inquirer after it published a misleading headline of its own, “Prescription opioids fail rigorous new test for chronic pain.”

“I suggest that you retract your article.  In its present form, it is propaganda not fact,” said Lawhern, a co-founder of the Alliance for the Treatment of Intractable Pain (ATIP). “Opioids have never been the first-line medical treatment of choice in lower back pain or arthritis. That role is served by anti-inflammatory meds, some of them in the prescription cortico-steroid family.  NSAIDs have a role to play, recognizing that they are actively dangerous in many patients if taken at high doses for long periods.  Hundreds of people die every year of cardiac arrest or liver toxicity due to high-dose acetaminophen or ibuprofen.” 

Who is Erin Krebs?  

Dr. Krebs is an associate professor at the University of Minnesota Medical School and a prolific researcher at the VA Medical Center in Minneapolis.

She was also an original member of the “Core Expert Group” – an advisory panel that secretly drafted the CDC’s controversial opioid guidelines while getting a good deal of input from the anti-opioid activist group Physicians for Responsible Opioid Prescribing (PROP). The guidelines recommend that opioids not be prescribed for chronic pain.

Krebs also appeared in a lecture series on opioid prescribing that was funded by the Steve Rummler Hope Foundation, which coincidentally is the fiscal sponsor of PROP. 

Some of her previous opioid research has been controversial. In a study published last year in the Annals of Internal Medicine, Krebs reviewed 67 studies on the safety and effectiveness of opioid tapering. Most of the studies were of poor quality, but nevertheless Krebs came to the conclusion that pain levels and the quality of life of patients “may improve during and after opioid dose reduction.”



“This review found insufficient evidence on adverse events related to opioid tapering, such as accidental overdose if patients resume use of high-dose opioids or switch to illicit opioid sources or onset of suicidality or other mental health symptoms,” wrote Krebs.

PROP founder Andrew Kolodny, MD, read the review and liked it, tweeting that “dangerously high doses should be reduced even if patient refuses.”

But forced opioid tapering is never a good idea, according to a top CDC official.

“Neither (Kreb’s) review nor CDC's guideline provides support for involuntary or precipitous tapering. Such practice could be associated with withdrawal symptoms, damage to the clinician–patient relationship, and patients obtaining opioids from other sources,” wrote Deborah Dowell, MD, a CDC Senior Medical Advisor, in an editorial also published in the Annals of Internal Medicine. 

As for Krebs’ contention that there is “insufficient evidence” of adverse events associated with opioid tapering, that notion may be put to rest next month when the VA releases a new study showing that tapering has led to a growing number of suicides by veterans.

In a summary of the findings, which will be presented at the Rx Drug Abuse & Heroin Summit, VA researchers report that “opioid discontinuation was not associated with overdose mortality, but was associated with increased suicide mortality.”  

Who and what should we believe in the neverending debate about opioids? PNN columnist Roger Chriss wrote about Krebs’ opioids vs. non-opioids study last year, when the initial reports of its findings came out. Roger said prescribing decisions are best left to physicians who know their patients’ medical conditions – not researchers, regulators or the news media.

“In reality, there is no ‘versus’ here. Opioids and NSAIDs are both valuable tools for chronic pain management. To pretend that one is inherently better than the other is to miss the essential point: Both work and should be available for use as medically appropriate,” Roger wrote. 

Do OTC Pain Relievers Dull Your Emotions?

By Pat Anson, Editor

Ibuprofen, acetaminophen and other over-the-counter pain relievers may do more than just dull your physical pain. They could also dull your emotional and cognitive senses, according to a new study.

Researchers at the University of California, Santa Barbara reviewed a small body of clinical studies that suggest OTC pain medications have an overlapping effect on us, both physically and emotionally.

One study, for example, found that acetaminophen makes people feel less empathy for others.

Research also found that women who took ibuprofen reported less social anxiety and hurt feelings after being excluded from a game or when writing about a time when they felt betrayed.

Yet another study found that acetaminophen lessens the discomfort of parting with a prized possession. When asked to set a selling price on an object they owned, individuals who took acetaminophen set prices that were cheaper than the prices set by individuals who took placebos.


"In many ways, the reviewed findings are alarming," wrote lead author Kyle Ratner, PhD, an assistant professor of psychology at UC Santa Barbara. "Consumers assume that when they take an over-the-counter pain medication, it will relieve their physical symptoms, but they do not anticipate broader psychological effects.

“Are more regulations needed? Should warnings be expanded on drug labels? At this point, drawing strong conclusions from the existing studies would be premature. Nonetheless, policymakers might start thinking about potential public health risks and benefits.”

Ratner and his colleagues say one place to start is to further study the effects of OTC analgesics on pregnant women. Recent research has found higher rates of autism and attention deficit disorder (ADHD) in young children whose mothers used acetaminophen while pregnant.

Acetaminophen -- also known as paracetamol – is the world’s most widely used over-the-counter pain reliever. It is the active ingredient in Tylenol, Excedrin, and hundreds of other pain medications. Ibuprofen is also widely used and can be found in brand name products such as Motrin and Advil.   

“Found in medicine cabinets across the world and used multiple times per week by people of all ages, genders, and ethnic backgrounds, these drugs are woven into modern life. Policymakers should take note of existing findings but not rush to judgment,” said Ratner.

The study is published online in the journal Policy Insights from the Behavioral and Brain Sciences.

Ibuprofen Linked to Reduced Male Fertility

By Pat Anson, Editor

If you’re a man who uses ibuprofen regularly for muscle pain or  headache, you could be compromising your ability to have children, according to a small new study.

French and Danish researchers enrolled 31 young male volunteers between the ages of 18 and 35 in the study, and gave about half of them 600 milligrams of ibuprofen twice a day -- the highest recommended dose. The other participants were given a placebo.

After just 14 days, the researchers noted signs of hormonal dysfunction in the men who took ibuprofen, who had high levels of luteinizing hormone, which the pituitary gland produces to stimulate testosterone production in the testicles. 

That condition -- known as hypogonadism -- is usually seen in older men who have low testosterone levels. Hypogonadism is associated with reduced fertility, lower sex drive, depression, fatigue and an increased risk of cardiovascular problems.


“We normally see this condition in elderly men, so it raises an alarm,” study co-author Bernard Jégou, PhD, of the French National Institute of Health and Medical Research, told The Guardian. “We are concerned about it, particularly for healthy people who don’t need to take these drugs. The risk is greater than the benefit.” 

Researchers say the disorder was mild in the ibuprofen group and went away when the men stopped taking ibuprofen. But they worry what would happen to men who take the pain reliever for longer periods. Many professional athletes regularly take high doses of ibuprofen.

“Our immediate concern is for the fertility of men who use these drugs for a long time,” said co-author David Møbjerg Kristensen, PhD, a professor of biology at the University of Copenhagen. “These compounds are good painkillers, but a certain amount of people in society use them without thinking of them as proper medicines.”

The study was published online in the Proceedings of the National Academy of Sciences .

“Ibuprofen appears to be the preferred pharmaceutical analgesic for long-term chronic pain and arthritis. Therefore it is also of concern that men with compensated hypogonadism may eventually progress to overt primary hypogonadism, which is characterized by low circulating testosterone and prevalent symptoms including reduced libido, reduced muscle mass and strength, and depressed mood and fatigue,“ the researchers warned.

The same team of researchers reported in earlier studies that aspirin, acetaminophen and ibuprofen affected the testicles of male babies born to mothers who took the drugs during pregnancy.

Ibuprofen is a widely used over-the-counter pain reliever found in brand name products such as Motrin and Advil.   

Painkiller Study Conducted at Poorly Rated Hospital

By Pat Anson, Editor

Over-the-counter pain relievers are just as effective as opioid medication in treating short-term acute pain in a hospital emergency room, according to a widely touted study published in the Journal of the American Medical Association (JAMA).

The study was relatively small – only 416 patients participated – and it was conducted at a New York City hospital with a poor history of pain care. Still, it's getting a lot of media coverage. “Milder pill may be best for pain” is the front page headline in the Los Angeles Times. “Drugstore pain pills as effective as opioids” said STAT News. “Opioids Not the Only Answer for Pain Relief” reported HealthDay.  


Researchers said patients with moderate to severe acute pain in their arms or legs got just as much pain relief after being given a combination of acetaminophen and ibuprofen than those who took hydrocodone, oxycodone or codeine. The study only measured pain relief for two hours.

Patients with sickle cell disease, fibromyalgia, neuropathy or any type of pain that lasted more than seven days were excluded from the study because researchers only wanted to focus on short term pain.

"Although this study focused on treatment while in the emergency department, if we can successfully treat acute extremity pain with a non-opioid combination painkiller in there, then we might be able to send these patients home without an opioid prescription," said lead author Andrew Chang, MD, a professor of emergency medicine at Albany Medical Center.

"We know that some patients who are given an opioid prescription will become addicted, so if we can decrease the number of people being sent home with an opioid prescription, then we can prevent people from becoming addicted in the first place."

What Chang, JAMA and the news reports all fail to mention is that the study was conducted at one of the worst hospitals in the nation. In an annual survey of Medicare patients, Montefiore Medical Center in New York City was given only one star (out of five possible), placing it in the bottom 2.44% of hospitals nationwide.

Montefiore was rated poorly on a variety of quality measures, including pain care. Only 64 percent of the patients treated there said their pain was “always” well controlled, compared to the national average of 71 percent.

‘Worst Hospital in the Entire City’

Many of the online reviews of Montefiore’s emergency room are scathing.

“Please do not come to the ER unless you want to die or are used to unsympathetic health professionals,” warned Amanda G. on Yelp.  “I have severe abdominal pain and I'm walking home in tears right now. I came in told the nurse there my symptoms and she couldn't have made it clearer that she couldn't care less.”

“This has to be the worst hospital in the entire city. The nurses in the ER are rude and don't care about your well being. The ER is filthy. People stacked on top of each other,” wrote Robert in a Google review.



“The emergency room sucks. The doctors sit around on the computers gossiping. I even overheard a few doctors saying ‘why aren’t we picking up patients?’ Meanwhile there’s a room full of patients not being taken care of. There’s a patient screaming for help and no one hears him. All the staff members just walk by him,” wrote Zoe D. on Yelp.

“Somebody told me this place was the equivalent of going to a hospital in Manhattan. They lied! I went to the emergency room today for chest pains, I ended up sitting there for four hours never to be seen by a doctor. I ended up walking out and leaving still with my chest pains,” said Phonz R. on Yelp.

“Their ER department is horrible. I went to the ER with my mom via ambulance, we got there (a little) before 1pm. Fast forward 1:58 in the morning she still wasn't put in a room,” wrote J.L. Eaddy on Google. “This was the absolute worst ER I've ever encountered. And I NEVER want to come back again. I wish I had the option to give it negative stars.”

Unfortunately, complaints such as these are not unusual in busy, urban teaching hospitals like Montefiore.  And not all the reviews are poor. U.S. News and World Report gave high rankings to Montefiore in a number of areas, although it didn’t specifically rank its emergency department. Montefiore was recently given a lukewarm “C” rating by the Leapfrog group, a non-profit that grades hospitals on quality and safety.  

Many pain patients have poor experiences in hospitals. In a survey of nearly 1,300 patients by PNN and the International Pain Foundation, over half rated the quality of their pain care in hospitals as either poor or very poor. About two-thirds of the patients said non-opioid pain medications were ineffective.

Hydrocodone Prescriptions Continue Falling

By Pat Anson, Editor

For the fifth year in a row, fewer prescriptions for the opioid painkiller hydrocodone were dispensed in the U.S. in 2016, according to a new report by the QuintilesIMS Institute, which tracks prescription drug use and spending.

The report adds further evidence that the nation’s overdose epidemic is being fueled by illegal opioids such as heroin and illicit fentanyl, not prescription painkillers.

About 7 million fewer prescriptions were filled last year for hydrocodone, which is usually combined with acetaminophen in Vicodin, Lortab, Lorcet, Norco, and other hydrocodone combination products.

As recently as 2012, hydrocodone was the #1 most widely dispensed medication in the nation, with 136 million prescriptions filled. Since then, hydrocodone prescriptions have fallen by over a third, to 90 million prescriptions.

Hydrocodone now ranks fourth, behind the thyroid drug levothyroxine (Synthroid), the blood pressure medication lisinopril (Zestril), and the statin atorvastatin (Lipitor).

Hydrocodone was reclassified by the DEA as a Schedule II controlled substance in 2014, making it harder to obtain. Opioid guidelines released last year by the CDC also probably had an impact, although hydrocodone prescriptions were falling long before the CDC and DEA acted.


Source: QuintilesIMS Institute

Prescriptions for hydrocodone and other opioids are likely to fall even further in 2017, because the DEA plans to reduce the supply of almost every Schedule II opioid pain medication by 25 percent or more "to prevent diversion." The 2017 quota for hydrocodone is being reduced by a third, to 58.4 million prescriptions, which the DEA considers an adequate supply.

Overall, QuintilesIMS reported 13 million fewer prescriptions for pain medicines in 2016, “as restrictions on prescribing and dispensing become increasingly common and impactful.” The company includes both narcotic and non-narcotic treatments in its pain medicine category.

Over 7 million more prescriptions were written last year for gabapentin (Neurontin), a medication originally developed to treat seizures that is now widely prescribed for neuropathy and other chronic pain conditions.  About 64 million prescriptions were written for gabapentin in 2016, a 49% increase since 2011.

More prescriptions are also being written for ibuprofen, a widely used pain reliever available both by prescription and in over-the-counter drugs. About 44 million prescriptions were filled for ibuprofen in 2016, a 19% increase since 2012.

The shift in prescribing away from opioids is hardly a surprise to pain sufferers. According to a recent survey of over 3,100 patients by PNN and the International Pain Foundation, over 70% said they were no longer prescribed opioids or were getting a lower dose since the CDC guidelines were released. About half of the doctors and pharmacists we surveyed also said they were writing or filling fewer opioid prescriptions, or had stopped them altogether.  

“My doctor cut me off hydrocodone cold turkey last fall leading to an overnight in the hospital emergency room,” a patient with chronic back pain and anxiety told PNN. “For years I have been stable on a mix of hydrocodone and Valium. Last October my doctor said he would only fill one prescription and asked me to make a choice so I stayed with the Valium.”

“With the VA allowing me only 2 hydrocodone per day now, I get very little exercise and stay in bed a lot,” a 70-year old veteran wrote. “My quality of life has gone down considerably. Before the changes, I stayed quite active taking 4 hydrocodone a day.”

“I had an interventional pain management doctor scream at me that the guidelines were mandatory and he refused to write for any type of opioids even though I've been on the same level of hydrocodone for several years,” another patient said.

“I took hydrocodone pain medicine for 25 years as the doctor proscribed. Never called in for more, now I'm having to go a pain doctor and get steroid shots every 3 months,” wrote a patient with lives with chronic back pain.

Overall spending on prescription drugs in the U.S. reached $323 billion in 2016, a 4.8% increase that is less than half the rate of the previous two years. The QuintilesIMS report blames the slowdown in growth on increased competition among drug makers and efforts to limit price increases.

“New medicines introduced in the past two years continue to drive at least half of the total growth as clusters of innovative treatments for cancer, autoimmune diseases, HIV, multiple sclerosis, and diabetes become accessible to patients,” said Murray Aitken, Senior Vice President and Executive Director, QuintilesIMS Institute.

Ibuprofen No Better Than Placebo for Back Pain

By Pat Anson, Editor

When it comes to treating back pain, anti-inflammatory drugs such as ibuprofen work no better than a placebo, according to new Australian study.

Researchers at the University of Sydney conducted a meta-analysis (a study of studies) of 35 clinical trials involving over 6,000 people with back pain, and found that non-steroidal anti-inflammatory drugs (NSAIDs) provide little benefit. The study was published in the Annals of the Rheumatic Diseases.

NSAIDs are effective for spinal pain, but the magnitude of the difference in outcomes between the intervention and placebo groups is not clinically important. At present, there are no simple analgesics that provide clinically important effects for spinal pain over placebo,” wrote lead author Gustavo Machado, PhD, of The George Institute for Global Health. “There is an urgent need to develop new drug therapies for this condition.”

Back pain is the world’s leading cause of disability, with about 80 percent of adults experiencing back pain at some point in their lives.

Opioids are usually not prescribed for simple back pain, leaving patients little alternative but over-the-counter pain relievers such as NSAIDs, a class of drugs that includes both aspirin and ibuprofen. NSAIDs are known to raise the risk of gastrointestinal and cardiovascular problems.

The Australian study found that NSAIDs reduced pain and disability somewhat better than a placebo or dummy medication, but the results were not statistically important.

"NSAIDs do not provide a clinically important effect on spinal pain, and six patients must be treated with NSAIDs for one patient to achieve a clinically important benefit in the short-term," wrote Machado. “When this result is taken together with those from recent reviews on paracetamol (acetaminophen) and opioids, it is now clear that the three most widely used, and guideline-recommended medicines for spinal pain do not provide clinically important effects over placebo.”

The study did not evaluate non-pharmacological treatments for back pain, such as exercise, physical therapy or chiropractic care.

NSAIDs are widely used to treat everything from fever and headache to low back pain and arthritis. They are found in so many different products -- such as ibuprofen, Advil and Motrin -- that many consumers may not be aware how often they use NSAIDs. 

NSAIDs Raise Risk of Dying From Endometrial Cancer

By Pat Anson, Editor

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have long been thought to reduce the risk of some cancers. But a surprising new study suggests that regular use of the pain relievers may actually raise the risk of dying for women with endometrial cancer.

Researchers at Ohio State University studied over 4,300 women with endometrial cancer, 550 of whom died during the five-year study. Those who used NSAIDs regularly and had Type 1 endometrial cancer had a 66 percent higher risk of death.

The research findings are published in the Journal of the National Cancer Institute.

"This study identifies a clear association that merits additional research to help us fully understand the biologic mechanisms behind this phenomenon. Our finding was surprising because it goes against previous studies that suggest NSAIDs can be used to reduce inflammation and reduce the risk of developing or dying from certain cancers," said co-author Theodore Brasky, PhD, a cancer epidemiologist at The Ohio State University Comprehensive Cancer Center.

Over 60,000 women are diagnosed with endometrial cancer in the U.S. annually, making it the fourth most common cancer in women and the sixth leading cause of cancer death.

Endometrial cancer begins in the lining of the uterus and grows outward to surrounding organs. Type 1 tumors are less aggressive and are typically confined to the uterus, while Type 2 tumors tend to be aggressive and are at greater risk of spreading.

In the OSU study, the risk of dying was statistically significant in women who reported past or current NSAID use, but it was strongest among patients who used NSAIDs for more than 10 years and had ceased using them prior to their cancer diagnosis.

Interestingly, the use of NSAIDs was not associated with mortality from more aggressive Type 2 cancers.

"These results are intriguing and worthy of further investigation," said co-author David Cohn, MD, director of the gynecologic oncology division at the OSU cancer center. “While these data are interesting, there is not yet enough data to make a public recommendation for or against taking NSAIDS to reduce the risk of cancer-related death."

Aspirin, ibuprofen and other NSAIDs are believed to lower the risk of some cancers by reducing inflammation, which slows the development of blood vessels that support the growth of cancer tumors. Inhibition of inflammation may have the opposite effect in endometrial cancer, but the reasons why are unclear.

Previous studies have shown that NSAIDs have a preventive effect on colorectal cancer and several other cancer types.

“Observational evidence of a chemopreventive effect of aspirin and other NSAIDs has been reported for esophageal, gastric, lung, breast, prostate, and colorectal cancer. Most of these cancers develop after age 60 years,”  researchers at the University of California Irvine reported in The Lancet.

“Given the apparent delay in the chemopreventive effect of NSAIDs (about 10 years), optimum treatment might start at age 40–50 years. Most individuals who develop premalignant lesions do so in their 50s and 60s, several years before the appearance of cancer, so this age range might be the best time for cancer prevention.”

Low-dose aspirin is also believed to have cardiovascular benefits. For that reason, the OSU researchers recommend that women keep taking the pain relievers.  

"It is important to remember that endometrial cancer patients are far more likely to die of cardiovascular disease than their cancer so women who take NSAIDs to reduce their risk of heart attack -- under the guidance of their physicians -- should continue doing so,” said Cohn.