NIH Study Finds Opioids Make Birds Sing

By Pat Anson, PNN Editor

Opioid medication has been associated with many things, from reduced pain and disability to constipation, addiction and overdoses. A new study has found that opioids also make birds sing.

Researchers at the University of Wisconsin-Madison say fentanyl, a potent synthetic opioid, causes “gregarious singing behavior” in starlings that sounds a bit like modern jazz. Starlings usually sing to attract mates, but these birds sang because they felt good.

“When I listen to these birds sing, it seems as if they are enjoying themselves,” Lauren Riters, PhD, a Psychology Professor at UW-Madison told Psychology Today. “To me, it sounds like free-form jazz riffs.”

The small study by Riters and her colleagues involved a total of 14 European starlings that were injected with either a placebo or small doses of fentanyl. Their findings, recently published in the journal Scientific Reports, suggest that fentanyl reduced stress and anxiety in the birds without making them intoxicated.

“We report that peripheral injections of the selective MOR (mu opioid receptor) agonist fentanyl cause dose-dependent increases in gregarious singing behavior in male and female starlings, while at the same time decreasing beak wiping, which is considered a sign of stress or anxiety. The fentanyl did not affect landings, indicating that fentanyl effects on behavior were not caused by gross deficits in motor activity,” Riters wrote.

Riters is a prolific researcher, participating in dozens of studies on the social activity of starlings, pigeons, quail, finches and other birds, much of it paid for with millions of dollars in federal grants from the National Institutes of Health (NIH).

This particular study was funded by a $338,000 NIH grant to examine “deficits in social communication.” The researchers say their findings could someday be used to treat humans suffering from autism, depression and anxiety. Not to make them sing, but to make them more social.

“Such disorders are characterized by social withdrawal and deficits in the ability to communicate appropriately in distinct social contexts. The proposed research will identify manipulations that stimulate context-appropriate social interactions, which can be used in the design of clinical interventions in humans with context-specific deficits in social communication,” the UW-Madison grant application states.

Some may scoff at her research, but Riters says there are lessons to be learned from it because songbirds, like humans, are social animals that enjoy singing for the same reasons we do: It helps us feel better.

“If this is the case, it would mean that our studies on songbirds are revealing an ancient, evolutionarily conserved neural circuit that regulates intrinsically rewarded social behaviors across many animals,’ she said.

Genetic Studies Could Pave the Way to New Pain Treatments

By Dr. Lynn Webster, PNN Columnist

Millions of Americans order DNA test kits to determine their ancestries. Knowing where you come from can be entertaining.  However, DNA testing can also help identify your risk of developing some diseases, including chronic pain.

Prenatal testing for genetic disorders is common. But genetic testing is also increasingly used to determine the risk of developing certain diseases or potential responses to specific drugs.

Currently, little is known about how to use genes to make an individual more or less sensitive to pain, or to learn the likelihood that someone will respond in a particular way to an analgesic based on their genetics. The good news is that we are on the cusp of gaining more information about the genes that control pain and pain treatments, and that knowledge should allow us to develop targeted pain therapies.

Most physicians still believe that everyone experiences pain in the same way. Research recently published in Current Biology discovered a gene—the so-called "Neanderthal gene"—that is associated with increased sensitivity to pain. Recognizing that a mutation of a specific gene can influence pain perception may be illuminating for many members of the medical profession.

The Individuality of Pain

Pain specialists have known for a long time that given the same stimulus, some people feel more pain than others. The truth is, there are several genes besides the Neanderthal gene that determine how an individual experiences pain. Some genes increase our sensitivity to pain, while other genes decrease it. Some genes influence how pain is processed, while other genes determine an individual's response to an analgesic.

The ability for an analgesic to provide pain relief in an individual is partially determined by the genetics of the receptor to which the pain medication binds. These genes are different from pain-sensitivity genes. For example, oxycodone may be very effective in relieving pain for one individual, but only partially effective for another.

Optimal pain relief requires recognition that each individual responds uniquely to a given analgesic. Doctors are beginning to provide gene therapy for cancer patients. Advancements in research may someday allow us to do the same for patients with pain.

The array of pain responses to the same stimulus is a major reason why one-size-fits-all dosing of pain medications is flawed. A given dose may leave some patients undertreated and others over-treated. Unfortunately, regulators who set arbitrary dose limits fail to understand or consider this biologic variability. 

Differing clinical responses to pain stimuli and medications underscore the need to individualize therapy. Knowing more about the biology of pain can help us to understand each individual’s response to painful stimuli and the variable response to any therapy.

The Heredity Nature of Pain

How we experience pain is a result of both environmental and genetic features. The genetic factors are what we inherit. Environmental factors — which we develop rather than inherit — include cultural attitudes, emotions, and individual responses to stress. Our personality and life’s experiences are included in the environmental factors that contribute to our experience of pain. Therefore, pain is a result of genetic and environmental interactions. Both can make an individual more or less sensitive to stimuli or analgesia. It is a complex and dynamic process.

The so-called Neanderthal gene is not a new discovery but was newly recognized in Neanderthals. The discovery is interesting, because it implies the gene has an evolutionary purpose. The gene is known as SCN9. There are several pain syndromes associated with the genetic mutations of the SCN9 gene, including some types of back pain and sciatica. Mutations of this gene can result in the total absence of pain or a heightened pain expression. The type of mutation determines the phenotype (or personal characteristics) of our response to a painful stimulus.

The Genetics of Analgesia

It is unclear how Neanderthals benefited biologically from increased pain sensitivity. As we know, acute pain elicits an alarm and is considered protective. It teaches us to avoid dangers that can threaten our life, and prevents us from walking on a broken leg until it heals sufficiently to bear our weight.

Evolution may not have been concerned about the effects of chronic pain. The Neanderthals' limited life expectancy, and the fact that their survival depended on strong physical conditioning, may have made chronic pain a non-issue. Chronic pain may have made survival difficult, or even impossible, for the Neanderthals.

The recent discovery that Neanderthals had the SCN9 gene should not be surprising, given the fact that modern humans shared a common ancestor with Neanderthals. The Neanderthal gene study is of particular interest to me, because I am working with several companies that are exploring potential drugs to affect the function of the SCN9 gene. The companies have different approaches, but they all are trying to find a way to dial down an individual's sensitivity to painful stimuli.

Since the SCN9 gene can be responsible for the total absence of all pain, as well as several extreme forms of pain, it may be reasonable to target the SCN9 gene to modulate pain.

My hope is that manipulation of the SCN9 gene will reduce pain sensitivity, making it easier to control pain by adjusting the dose and type of drug we prescribe.

It is possible one or more drugs that target the SCN9 gene will be available within the next 4-6 years. If that occurs, it could be game changer for people in pain. We can then thank our Neanderthal ancestors for the evolutionary gift. 

Lynn R. Webster, MD, is a vice president of scientific affairs for PRA Health Sciences and consults with the pharmaceutical industry. He is author of the award-winning book, “The Painful Truth,” and co-producer of the documentary, “It Hurts Until You Die.” You can find Lynn on Twitter: @LynnRWebsterMD

Neanderthal Gene Makes Us More Sensitive to Pain

By Pat Anson, PNN Editor

The popular image of Neanderthals is that they were brutish and primitive hunter-gatherers who scratched out an existence in Eurasia 500,000 years ago. That may be a bit unfair. Anthropologists say Neanderthals were more intelligent than we give them credit for, lived socially in clans, and took care of each other. They also co-existed for tens of thousands of years with modern humans, competing for food and sometimes interbreeding before the Neanderthals were driven to extinction.

Neanderthals may have had the last laugh though, because we’ve inherited a gene from them that makes some of us more sensitive to pain, according to a new study published in the journal Current Biology. The gene affects the ion channel in peripheral nerve cells that send pain signals to the brain.

“The Neandertal variant of the ion channel carries three amino acid differences to the common, ‘modern’ variant,” explains lead author Hugo Zeberg, a researcher at the Max Planck Institute for Evolutionary Anthropology in Germany. “While single amino acid substitutions do not affect the function of the ion channel, the full Neandertal variant carrying three amino acid substitutions leads to heightened pain sensitivity in present-day people.”

Zeberg and his colleagues say about 40% of people in South America and Central America have inherited the Neanderthal gene, along with about 10% of people in East Asia. Using genetic data from a large population study in the UK, they estimate that only about 0.4% of present-day Britons have the full Neanderthal variation of that specific gene.

“The biggest factor for how much pain people report is their age. But carrying the Neandertal variant of the ion channel makes you experience more pain similar to if you were eight years older,” said Zeberg.

The Neanderthal ion channel in peripheral nerves is more easily activated by pain, which may explain why modern-day people who inherited it have a lower pain threshold. Exactly how the gene variation affected Neanderthals back in the day is unknown.

“Whether Neandertals experienced more pain is difficult to say because pain is also modulated both in the spinal cord and in the brain,” said co-author Svante Pääbo. “But this work shows that their threshold for initiating pain impulses was lower than in most present-day humans.”

It’s possible the heightened sensitivity to pain acted as an early warning system for Neanderthals, alerting them to injuries and illnesses that needed attention. Neanderthals lived a hard life. About 80% of Neanderthal remains show signs of major trauma from which they recovered, including attacks by bears, wolves and other large animals.

Neanderthals made extensive use of medicinal plants. The remains of a Neanderthal man in Spain with a painful tooth abscess showed signs that he chewed poplar tree bark, which contains salicylic acid, the active ingredient in aspirin.  

Newly Discovered Blood Cells Predict Rheumatoid Arthritis Flareups

By Pat Anson, PNN Editor

A simple blood test could give an early warning to rheumatoid arthritis sufferers that their symptoms are about to get worse, according to a new study published in the New England Journal of Medicine.   

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which the body’s own defenses attack joint tissues, causing pain, inflammation and bone erosion. The symptoms come in waves, with periods of remission interspersed with painful flareups.

Researchers at Rockefeller University have identified a new type of cell – called "PRIME cells" – that dramatically increase in the blood of RA patients a week before a disease flareup.

“If we can reliably identify these new cells in patients, we may be able to tell them ‘You’re about to have a flare,’ so they can prepare themselves,” says lead author Robert Darnell, MD, a neuroscientist at Rockefeller’s Howard Hughes Medical Institute. “This would make flares less disruptive and easier to manage.”

Over a four-year period, researchers analyzed hundreds of blood samples from four RA patients, who collected the blood at home using finger pricks and sent them to Darnell’s lab. Each participant also kept a record of their symptoms to identify when flares occurred.

National Institutes of Allergy and Infectious Diseases

Darnell and his colleagues looked for molecular changes in the blood prior to the onset of symptoms, and saw an increase in immune cells two weeks prior to a flare. That was not surprising, because the cells are known to attack the joints of RA patients.

But in samples collected one week before a flare, researchers saw an increase in cells that didn't match the genetic signature of any known type of blood or immune cell. The RNA signature of the cells resembled that of bone, cartilage or muscle cells – which are not typically found in blood.

“We were so surprised to see that the genes expressed right before a flare are normally active in the bone, muscle, and extracellular matrix -- strange pathways to find in blood cells,” said coauthor Dana Orange, MD, a rheumatologist at Rockefeller. “That really piqued our interest.”

Darnell's team named their discovery PRIME cells because they are "pre-inflammation mesenchymal" cells -- a type of stem cell that can develop into bone or cartilage. Notably, while PRIME cells accumulated in the blood before flares, they disappeared during them.

Researchers say PRIME cells have RNA profiles that are strikingly similar to synovial fibroblasts, which are found in the tissue lining of joints and are known to play a role in causing RA symptoms. In experiments on laboratory mice, fibroblasts that were removed from inflamed joints and transplanted into healthy mice caused them to become arthritic too.

Researchers are now recruiting RA patients for a larger study to confirm whether PRIME cells can predict a flare. If the cells do act as a precursor, it could lead to the development of drugs that target PRIME cells and stop flares before symptoms worsen.

“For doctors and patients, intervention before a flare up is always better than just treating symptoms,” says Darnell. “If these cells are the antecedents to joint sickness, they become a potential target for new drugs.”

New Imaging Better Identifies Sources of Chronic Pain

By Pat Anson, PNN Editor

A new approach to diagnostic imaging that combines the use of positron emission tomography (PET) and magnetic resonance imaging (MRI) could help identify the causes of chronic pain better than current methods, according to a new study at Stanford University School of Medicine.

PET scans that identify increased glucose metabolism in the body – known as 18F-FDG PET -- are currently used by oncologists to detect where tumors are located. Stanford researchers say the same approach could also be used to more precisely locate inflammation in injured nerves and muscles.

"In the past few decades, we have confirmed that anatomic-based imaging approaches, such as conventional MRI, are unhelpful in identifying chronic pain generators," said Sandip Biswal, MD, an associate professor of radiology at Stanford University School of Medicine.

"We know that 18F-FDG PET has the ability to accurately evaluate increased glucose metabolism that arises from to acute or chronic pain generators. As such, in our study we examined PET/MRI as a potential solution to determine the exact molecular underpinnings of one's pain."

In the study, 65 chronic pain patients underwent 18F-FDG PET and MRI scans from head to toe. The PET/MR images were then evaluated by two radiologists to determine if more glucose uptake occurred in painful areas or in other parts of the body. Increased glucose metabolism was detected in 58 of the 65 patients.

One such patient was an adult male who lived with decades of chronic pain in his neck as a result of an injury experienced at birth. PET/MR scans — such as the image on the right — identified muscles in his right neck near a spinal nerve where there was elevated glucose uptake.

This finding encouraged a surgeon to explore the area. The surgeon found a collection of small arteries wrapped around the nerve. When the arteries were ablated (removed) by the surgeon, it relieved pressure on the nerve and the patient reported tremendous relief.

Cipriano, et al., Stanford University

As a result of PET/MR imaging, 40 patients in the study had their pain management plans modified, including some who had procedures that their doctor had not anticipated, such as surgery to relieve foot pain and the placement of blood patches to treat cerebrospinal fluid leaks.

"The results of this study show that better outcomes are possible for those suffering from chronic pain," said Biswal. "This clinical molecular imaging approach is addressing a tremendous unmet clinical need, and I am hopeful that this work will lay the groundwork for the birth of a new subspecialty in nuclear medicine and radiology.”

Biswal recently presented his findings at the annual meeting of the Society of Nuclear Medicine and Molecular Imaging. They’ve also been published in the Journal of Nuclear Medicine.

Can a Cuddly Robot Reduce Pain and Increase Happiness?

By Pat Anson, PNN Editor

A cuddly therapeutic robot – designed to look and act like a baby seal – can improve mood and reduce moderate to severe pain in people, according to a new study.

The PARO robot emits seal-like sounds and moves its head and flippers in response to being touched and spoken to. Since its introduction in Japan in 2005, the PARO has become a virtual pet for thousands of people around the world who live in places where real animals are not allowed, such as nursing homes, elder care centers and hospitals.

Since social contact between humans can alleviate pain, researchers at Israel’s Ben-Gurion University (BGU) designed a study to see if the PARO robot could have similar effects in 83 healthy young volunteers.

It’s important to note that anyone with acute or chronic pain was disqualified from participating in the study. Pain was induced in the volunteers by exposing them to a heat probe.

Those who were allowed to touch and pet the PARO rated their pain levels significantly lower than those who had no physical contact with the robot. They also reported significantly higher levels of happiness.

SCIENTIFIC REPORTS

“Another possible explanation of our finding is that the interaction with PARO distracted the participants away from pain. Changing the focus of attention away from painful stimuli was shown to be efficacious in altering pain perception,” wrote lead author Shelly Levy-Tzedek, PhD, who heads the Cognition, Aging & Rehabilitation Laboratory at the Ben Gurion University.

"These findings offer new strategies for pain management and for improving well-being, which are particularly needed at this time, when social distancing is a crucial factor in public health."

To their surprise, BGU researchers also found lower oxytocin levels in those who interacted with PARO compared to those in a control group who did not meet the robot. Oxytocin is known as the “love hormone" because it is elevated in romantic partners or mothers bonding with their children -- so a lower level of oxytocin wasn't expected.

Researchers speculated in the journal Scientific Reports that oxytocin could also be a stress marker and that lower levels of the hormone may facilitate trust and sociability.

“In summary, this study indicates that social touch with PARO robot alleviates pain, increases happiness state and decreases oxytocin levels. Participants with higher perceived ability to communicate with PARO display greater pain alleviation as well as lower oxytocin levels,” researchers said.

A 2017 study also found that touching can have an analgesic effect. Young healthy couples who held hands while being subjected to mild heat felt less pain than those who were not touching or sitting in separate rooms.  

How Poppy Seed Muffins Could Get You Flagged by a Drug Test

By Pat Anson, PNN Editor

If you’re a patient who is prescribed opioid pain medication, you may have been warned not to eat poppy seed muffins or bagels before a drug test.

The tiny black seeds may contain trace amounts of morphine and codeine, which can be detected in a drug screen and wreak havoc with your medical care. A positive test could result in your doctor taking you off opioid medication or even dropping you as a patient.

Is the poppy seed warning accurate or just an urban myth? A group of researchers wanted to find out, so they ran a series of tests to measure opiate levels in commercially available poppy seeds. They washed, steamed and heated the seeds to see how that changed concentrations of three opium alkaloids: morphine, codeine and thebaine.

Washing or soaking the poppy seeds in water significantly reduced the presence of all three opium alkaloids. So did heating the seeds at a temperature of 392 F for at least 40 minutes.

However, baking the seeds in a muffin for 16 minutes at 392 F didn't significantly change the opium alkaloids, possibly because the internal and external temperatures of the muffins reached only 211 F and 277 F, respectively.

“Baking had no significant effect on concentrations of opium alkaloids. Overall, these results indicate that opium alkaloids may not be significantly affected by baking or steam application and that poppy seeds may require water washing or extended thermal treatment to promote reduction of these compounds,” said lead author Benjamin Redan, PhD, a research chemist who works in the FDA’s Institute for Food Safety and Health.

Redan says poppy seed muffins would have to be baked for at least two hours just to reduce morphine and codeine levels by 50 percent – which is not a recipe for passing a drug test or for baking tasty muffins.

The findings were recently published in the American Chemical Society’s Journal of Agricultural and Food Chemistry.

Poppy Seed Tea

Researchers and law enforcement agencies have been paying more attention to the lowly poppy seed because of anecdotal reports of people using the seeds to brew a potent tea that can be used for pain relief or to get high.

Late last year, Drug Enforcement Administration classified unwashed poppy seeds as a Schedule II controlled substance. While the poppy plant has long been classified as an illegal substance, the unwashed seeds were exempt because they were not perceived as a problem until recently.

“Individuals wishing to extract the opium alkaloid content from unwashed poppy seeds, use the seeds to create a tea, which contains sufficient amounts of alkaloids to produce psychoactive effects,” the DEA said. “Unwashed poppy seeds are a danger to the user and their abuse may result in unpredictable outcomes including death.”

The Internet is filled with stories about people experimenting with poppy seed tea. One alternative health website even has a recipe for making poppy seed tea that comes with a stark warning.

“Unfortunately, the abuse of or having insufficient knowledge about this tea has led to a few fatal incidences,” the recipe warns.

Tennant Foundation Launches Intractable Pain Research and Education Project

By Pat Anson, PNN Editor

One of the pioneers of pain management in the United States is hoping to draw more attention to intractable pain and how it differs from chronic pain. While chronic pain lasts for 90 days or more, intractable pain can persist for years, decades or even a lifetime. Many doctors fail to distinguish between the two, which leads to gaps in diagnosis and treatment.

“The pain field has been woefully negligent about this. They talk about symptomatic treatment of what to do to relieve chronic pain, but in order to deal with intractable pain syndrome you’ve got to treat the underlying cause,” says Dr. Forest Tennant, whose foundation has just released a new report called “The Intractable Pain Syndrome: A Call for Recognition and Prevention.”

“We’ve worked on it for quite some time with the goal of having every patient, doctor, nurse and family understand it. And to try and bring things out in language that is understandable by everybody.”

“This was a labor of love for all of us, born from a sincere desire to bring recognition, treatment and prevention to this devastating syndrome,” says co-author Ingrid Hollis, whose son was treated by Tennant for Arachnoiditis and Ehlers-Danlos Syndrome. “We have learned so much through the years, and I believe there is much that can be done to prevent intractable pain syndrome from developing and progressing when it occurs.”

“One of the reasons we’re doing this is to call for early recognition and vigorous treatment,” Tennant told PNN. “Someone who has this for two, five or twenty years, you can’t expect much reversal. But those people who have these conditions for six months or a year, they have a great ability to reverse a great deal of this. The earlier the treatment, the better the outcome.”

Left untreated, Tennant says intractable pain syndrome (IPS) can lead to chronic inflammation in the central nervous system that is difficult to reverse.  The inflammation not only causes constant pain, it leads to loss of brain tissue and creates dysfunction in the neurologic, cardiovascular, hormone and immune systems.  

“We’ve known for centuries that a painful injury will create what amounts to electricity. And too much electricity causes inflammation and inflammation causes tissue destruction,” says Tennant. “Intractable pain syndrome does change their basic physiology by virtue of altering physically the neurotransmitter systems that are in the brain and spinal cord. That is really the difference. And this is very objective. It’s measurable. It’s visible. It’s clear when its present.”

Tennant says these “pockets” of inflammation can be seen on MRI’s and brain scans. Someone suffering from simple chronic pain won’t have them, but people with intractable pain will.

There are five basic conditions that can cause IPS:

1. Arachnoiditis, a chronic inflammation of spinal nerves

2. Genetic connective tissue/collagen disorders such as Ehlers-Danlos Syndrome (EDS)

3. Reflex Sympathetic Dystrophy (RSD), also known as Complex Regional Pain Syndrome (CRPS)

4. Brain injuries caused by strokes or head trauma

5. Serious end-stage osteoarthritis of the spine, hips, knees or feet.

Other possible causes of IPS are porphyria, sickle cell disease, Lyme disease, interstitial cystitis, and some rare genetic disorders.   

IPS Can Be Reversed

Long recognized as incurable, Tennant says intractable pain can be reversed if diagnosed and treated early. He has pioneered some new treatments for IPS, including hormone supplements, physical therapy and better nutrition.

“Our project hopes to educate people about what they can do to reverse a lot of this,” Tennant told PNN. “Step number one is you’ve got to have vigorous treatment of the underlying cause of pain. The arachnoiditis has to be treated. The arthritis has to be treated. The RSD has to be treated. In other words, vigorous treatment of the underlying condition.

“Step number two, there are specific things they can do to slow down the inflammation inside the central nervous system. We know the body makes hormones inside the brain and spinal cord that can reduce the inflammation inside the central nervous system and regrow some of the tissue that’s been lost. People say you can’t do that, but oh yes, you can. There are studies that show this and we see this clinically.”

“I strongly believe that Dr. Tennant's concept of how intractable pain develops and progresses is absolutely correct.  His work in identifying the causes, developing diagnostic criteria, and figuring out a treatment protocol provides what doctors need to know to help people with intractable pain,” says co-author Kristen Ogden, whose husband Louis was treated by Tennant for a complex autoimmune condition.

“Louis' treatment with Dr. Tennant allowed him to improve so much in so many ways. Very effective pain control, greatly improved function and the best quality of life he ever had as an adult.  I am sure that very few people have any idea at all how much a seriously ill pain patient can improve and even regain lost function and capabilities if they have the right medical regimen that meets their needs.”

Tennant retired from clinical practice in 2018, the year after his home and office were raided by the DEA as part of an investigation into his opioid prescribing. No charges were ever filed against him. While Tennant no longer sees patients, he is continuing his research into the treatment of IPS – which notably downplays the use of opioids.

“The answer to opioid use is treating the syndrome rather than just giving symptomatic relief. Opioids are symptomatic drugs,” explains Tennant. “What we’re saying is, identify this and try to treat the condition. Don’t just throw a bunch of symptomatic antidepressants, opioids and other interventions at it. Start trying to look at it physiologically and pathologically, and treat it like we do other syndromes.”    

To learn more about the Tennant Foundation’s Intractable Pain Syndrome Research and Education Project, click here. 

Dr. Tennant and the Tennant Foundation have given financial support to Pain News Network and are currently sponsoring PNN’s Patient Resources section.  

Sex Bias Persists in Pain Research

By Pat Anson, PNN Editor

It’s long been known that women are more likely than men to have chronic pain conditions such as fibromyalgia, rheumatoid arthritis, irritable bowel syndrome (IBS) and migraine. Women are also more likely to feel more severe, recurring and longer lasting pain.

Why then are women less likely to receive pain treatment? And why are some treatments less effective for women?

One obvious reason is that men and women have different biology and process pain differently. Another is a “blind spot” in pain research, which is more focused on studying males than females, according to a new review published in the journal Nature Reviews Neuroscience.

"The pain literature is biased such that, because of the overwhelming use of male animals in experiments, we are increasingly learning about the biology of pain in males. And wrongly concluding that this is the biology of pain. It's only the biology of pain in males," says author Jeffrey Mogil, PhD, a Professor of Psychology and Anesthesia at McGill University in Montreal.

Mogil reviewed over 1,000 research articles published in the journal Pain between 2015 and 2019, and found a distinct change in the sex of laboratory animals used in research. In 2015, for example, 80 percent of the studies only used male rodents. By 2019, half of studies were male-only.

SOURCE: Nature Reviews Neuroscience.

The trend towards using both male and female animals may sound like a promising change in research design. But when Mogil looked more closely at sex differences in pain literature, he found clear evidence that a male bias still exists in pain research.

"The very ideas we come up with for experiments, are based on experiments in males and therefore they work in males and not in females,” says Mogil.

Even in studies that included both male and female rodents, Mogil found that the research was often geared toward the males’ response. In experiments that “worked out” -- meaning the scientific hypothesis being tested was found to be true -- over 72% of the male rodents had a positive response, while only about 28% of the female rodents did. That strongly suggests the research was biased even before the experiments began.

"If there were no bias in the literature and there were a number of papers where the experiment worked in one sex and not the other, it should work in females just as often as in males,” explained Mogil. “Why has this happened? Because the hypothesis that that experiment tested out was generated based on prior data from experiments on only males. So, of course, it only worked in males."

The bias in research can have lasting effects on pain treatment and may help explain why some analgesic medications are more effective when taken by men.

"This research suggests that lots of what's in the pipeline right now, if it works in anyone at all, will largely be men. Whereas the clear majority of chronic pain patients have been and continue to be women," Mogil said.

Steps have been taken to reduce bias in pain research. If they want to get government funding, researchers in the United States, Canada and several European countries are now required to evaluate both sexes in their research. Mogil is optimistic those policies will eventually make a difference, but it may take awhile to undo decades of research that focused primarily on male animals.

“Performing biomedical experiments in both sexes is not only the ethically correct thing to do but also the scientifically correct thing to do, especially if we wish to reverse the particularly unimpressive track record of clinical trial success in the past few decades,” Mogil wrote.

UK Study Finds Weather Can Worsen Chronic Pain

By Pat Anson, PNN Editor

Do you feel “under the weather” when its rainy and cold outside? About 75% of chronic pain sufferers believe certain weather conditions can aggravate their pain. Some even think they can predict a storm coming because they “can feel it in their bones.”

A new analysis of weather patterns in the United Kingdom suggests there may be some truth to those old clichés.

For 15 months, researchers at the University Manchester collected data from over 10,500 UK residents, who recorded their daily pain levels on a smartphone app. The GPS location of their phones was then compared to local weather conditions.

The study found a modest association between weather and pain, with people more likely to feel pain on days with low barometric pressure – and the wet and windy weather that usually comes with it.

The key appears to be the upper level jet stream – a narrow band of air currents that circle the globe several miles above the earth. On days when the jet stream was aimed right at the UK, with above normal wind, humidity and precipitation, about 23% of people reported more pain.

But when the jet stream blew north of the UK, and pressure was above normal with less humidity and precipitation, only 10% of people reported higher pain levels.

“Although the weather may not be the primary cause of people’s pain, our results through multiple independent methodologies demonstrate that weather does modulate pain in at least some individuals,” lead author David Schultz reported in the Bulletin of the American Meteorological Society.

“The results of this project should give comfort and support to those who have claimed that the weather affects their pain, but have been dismissed by their friends, their coworkers, and even their doctors.“

The new analysis builds on earlier research from the Cloudy With a Chance of Pain study, which is the largest in both duration and number of participants to examine the link between weather and pain.  Previous studies have found little or no association between the two.

A 2014 Australian study, for example, found that acute low back pain was not associated with variations in temperature, humidity and rain.  And a 2013 Dutch study concluded that weather had no impact on fibromyalgia symptoms in women.

“Part of the reason for this lack of consensus is that previous researchers have treated the different measures of the weather such as pressure, temperature, humidity separately, which assumes that one could vary the temperature while holding all of the other weather measures fixed. Of course, the real atmosphere does not behave like this, as all the variables are changing simultaneously,” says Schultz.

Schultz and his colleagues plan to further study the data to see how environmental conditions modulate pain, insight that could be used to develop better treatments and individualized pain forecasts.

Experimental Treatment Targets Neuropathic Pain

By Pat Anson, PNN Editor

Researchers in Denmark have developed a promising new compound to treat neuropathy that targets the hyper-sensitized nerves that cause chronic pain. The experimental compound – a peptide called Tat-P4-(C5)2 -- has only been tested in mice, but researchers hope to begin clinical trials on humans soon.

"We have developed a new way to treat chronic pain. It is a targeted treatment. That is, it does not affect the general neuronal signaling, but only affects the nerve changes that are caused by the disease," says Kenneth Lindegaard Madsen, PhD, Associate Professor at the University of Copenhagen.

"We have been working on this for more than ten years. We have taken the process all the way from understanding the biology, inventing and designing the compound to describing how it works in animals, affects their behaviour and removes the pain.”

Madsen and his colleagues recently published their findings in the journal EMBO Molecular Medicine .

The image below shows the compound Tat-P4-(C5)2 after it is injected into the spinal cord. The compound (purple) penetrates the nerve cells of the spinal cord (yellow), but not the surrounding cells (the cell nuclei are blue). The compound blocks neuropathic pain signals – the kind associated with diabetic neuropathy, shingles, phantom limb pain and chemotherapy-induced pain — from being sent to the brain.

UNIVERSITY OF COPENHAGEN

In a previous study, the researchers showed in an animal model that use of the compound can also reduce tolerance and the risk of addiction. They believe the compound will be more effective and safer than the anti‐convulsants, antidepressants and opioid medications now used to treat neuropathy.

"The compound works very efficiently, and we do not see any side effects. We can administer this peptide and obtain complete pain relief in the mouse model we have used, without the lethargic effect that characterises existing pain-relieving drugs," said Madsen.

"Now, our next step is to work towards testing the treatment on people. The goal, for us, is to develop a drug, therefore the plan is to establish a biotech company as soon as possible so we can focus on this."

Is Your Pain Tolerable?

By Pat Anson, PNN Editor

There has long been controversy over the way pain is measured by healthcare providers. Critics say the two most widely used methods, the numeric 0 to 10 pain scale and the Wong Baker Pain Scale, are too subjective because they rely on patients to self-report their pain levels.

Some even claimed that asking patients about their pain encourages excess opioid prescribing. There was never any evidence to support that argument, but in 2017 the Centers for Medicare and Medicaid Services (CMS) caved into political pressure and dropped three survey questions that asked Medicare patients about the quality of pain care they received in hospitals.   

A new method of measuring pain is now being proposed, one that is designed to reduce opioid prescribing and other pain treatments. It hinges on a simple question:

“Is your pain tolerable?”

In a new study published in JAMA Network Open, researchers say asking patients that question could help doctors decide whether opioids and other treatments are really necessary.

"Because of concerns about overtreatment of pain with opioids there has been an enormous effort to rethink how we ask patients about pain," says lead author John Markman, MD, director of the Translational Pain Research Program at the University of Rochester Medical Center.

"Knowing that patients consider their pain to be tolerable, physicians wouldn't necessarily prescribe a medication with serious risks or expose them to surgery.”

Markman and his colleagues asked 537 primary care patients if their pain was tolerable, and then had them rate the intensity of their pain on the 0 to 10 scale.

Most patients who had mild pain (a score of 1 to 3) or moderate pain (4 to 6) said their pain was tolerable. Even with a severe pain score of 7, nearly 40% said their pain was tolerable. But after that, at level 8 or higher, severe pain becomes less and less tolerable.

JAMA NETWORK OPEN

“Our findings confirmed the intuitive assumption that most patients with low pain intensity find their pain tolerable,” Markman wrote. “In contrast, the tolerability of pain rated between 4 and 6 varies substantially among patients. In this middle range, if a patient describes pain as tolerable, this might decrease the clinician’s inclination to initiate higher-risk treatments.  A substantial subgroup of patients with severe pain reported their symptoms as tolerable.”

One weakness of the tolerable question is that it measures pain at a single point in time – and chronic pain patients often experience flares that can make their pain intolerable. It also assumes that every patient is alike and has the same level of tolerance.

Markman says numeric pain scales have "very little relevance" when patients who have lived with chronic pain for several years visit their doctors.

"If, instead, a patient could say 'my pain is tolerable when I'm doing this but intolerable when I'm doing that,' and it's in the context of that patient's life, I frankly think that's much more useful, and is what doctors really want to know," Markman said.

"In order to transform how we treat pain to make treatments safer and more effective, we need to start with a reformation in how we ask patients about pain."

PROP Linked to New Federal Opioid Study

By Pat Anson, PNN Editor

A small but influential group of anti-opioid activists continues to play an outsized role in guiding federal policy on the use of opioid pain medication.

The latest example is a new report by the Agency for Healthcare Research and Quality (AHRQ) on the effectiveness of opioids in treating chronic pain. In a lengthy review of over 150 clinical studies, AHRQ researchers concluded that opioids were no more effective in treating pain than nonopioid medication, and that long-term use of opioids increases the risk of abuse, addiction and overdose, especially at high doses.

The findings are essentially the same as those in a draft report released by the AHRQ last year. What’s different is that the agency finally disclosed the authors of the report and the outside advisors they consulted with. They include a cabal of academic researchers and physicians with biased views about opioids that federal agencies keep bringing in as consultants.   

The AHRQ’s report confirms what PNN reported in November. The study was led by Dr. Roger Chou, a primary care physician who heads the Pacific Northwest Evidence-based Practice Center at Oregon Health & Science University.

Most public health researchers keep a low profile to avoid accusations of bias, but Chou has been a vocal critic of opioid prescribing for years. In a 2019 podcast, for example, Chou said the benefits of opioids were “clinically insignificant” and the medications were often quite harmful.

“The impact of prescription opioids in terms of mortality and substance use disorder and all the other things that come along with it have really been quite staggering,” he said.

Chou also served on a state task force last year that supported a rigid opioid tapering policy. If adopted, the policy would have forced thousands of Oregon’s Medicaid patients off opioids.

DR. ROGER CHOU

“I don’t think there’s anything compassionate about leaving people on drugs that could potentially harm them,” Chou said.

Collaboration with PROP

Chou has collaborated on several occasions with members of Physicians for Responsible Opioid Prescribing (PROP), an advocacy group that seeks to reduce the use of opioid medication. PROP has never disclosed its donors or funding.

Last year Chou co-authored an op/ed with PROP President Dr. Jane Ballantyne and PROP board member Dr. Anna Lembke that encourages doctors to consider tapering “every patient receiving long term opioid therapy.”

In 2011, Chou co-authored another op/ed with PROP founder Dr. Andrew Kolodny and PROP vice-president Dr. Michael Von Korff. 

The article was prescient because it called for a major overhaul of opioid guidelines that were then primarily developed by pain management specialist organizations.

“Guidelines for long-term opioid therapy should not be developed by the field of pain medicine alone.”

— Kolodny, Chou, et al 2011

“Guidelines for long-term opioid therapy should not be developed by the field of pain medicine alone. Rather, experts from general medicine, addiction medicine, and pain medicine should jointly reconsider how to increase the margin of safety,” they said.

That major overhaul came in 2016, when the Centers for Disease Control and Prevention released its controversial opioid guideline, which soon displaced all of the other guidelines. Chou was one of the co-authors of the CDC guideline – so it’s not altogether surprising that the AHRQ study reaffirms many of the CDC’s conclusions.

“Findings support the recommendation in the 2016 CDC guideline that opioids are not first-line therapy and to preferentially use nonopioid alternatives,” Chou and his colleagues wrote.

In preparing the AHRQ study, researchers sought input from a dozen outside experts, who served as technical experts and peer reviewers. Three of the 12 are PROP board members: Drs. Mark Sullivan and David Tauben were technical experts, and PROP vice-president Dr. Gary Franklin was a peer reviewer. Sullivan, Tauben and Franklin are all professors at the University of Washington, and played prominent roles in the development of Washington state’s opioid prescribing regulations, which are some of the toughest in the nation.

Another peer reviewer was Dr. Erin Krebs, an associate professor at the University of Minnesota Medical School. Krebs was the lead author of a controversial 2018 study that found non-opioid pain relievers worked better than opioids in treating osteoarthritis pain. While some critics said the study was poorly designed and amounted to junk science, it drew praise from Chou.

"The fact that opioids did worse is really pretty astounding," Chou told the Chicago Tribune. "It calls into question our beliefs about the benefits of opioids." 

In addition to her work as a researcher, Krebs also appeared in a lecture series on opioid prescribing funded by the Steve Rummler Hope Foundation, which lobbies against the use of opioids. The non-profit foundation is the fiscal sponsor of PROP, and Kolodny and Ballantyne both serve on its medical advisory committee.

If these intertwining connections are making your head spin, there’s more.

Core Expert Group

Ballantyne, Franklin and Krebs served on the “Core Expert Group” that advised the CDC when it drafted its opioid guideline, and Tauben was on the CDC’s peer review panel. Kolodny and yet another PROP board member, Dr. David Juurlink, were part of a “Stakeholder Review Group” that provided input to the CDC.

When PNN filed a request under the Freedom of Information Act (FOIA) to see what kind of advice the Core Expert Group gave to the CDC, we were stiff-armed by the agency. The CDC sent us nearly 1,500 pages of documents, but most were so heavily redacted they were completely blank.    

Even financial conflict of interest statements were scrubbed of information, with the CDC citing “personal privacy” and “deliberative process privilege” as reasons not to provide them in full.

At least two unidentified members of the Core Expert Group worked for or consulted with organizations with an interest in opioids or other controlled substances. One of those individuals also provided “expert opinion or testimony,” which has become a lucrative sideline for some PROP members.

Critics wonder why federal health agencies keep bringing in consultants with obvious biases and conflicts of interest.

“The AHRQ review presents itself as an objective scientific analysis of the medical literature. In my opinion, the document is arguably contaminated with a political agenda,” says Dr. Dan Laird, a physician attorney in Las Vegas. “Some of those involved in the review could be perceived by the chronic pain community as having strong anti-opioid political views and biased ideas about the meaning and treatment of chronic pain.

“Most importantly, there is no input whatsoever from the chronic pain community in the review. There are certainly chronic pain patients with academic credentials that would qualify them to conduct a literature review. Several highly regarded academic physicians and scientists, known for opioid moderatism, are conspicuously absent as investigators, peer reviewers, or technical experts; these include pain medicine academicians such as Drs. Michael Schatman, Sean Mackey, Stefan Kertesz, and Vanila Singh.”

AHRQ Conflict Policy

If a peer reviewer or technical expert has a financial or professional conflict of interest, that does not automatically disqualify them in the eyes of the AHRQ, which will retain them “because of their unique clinical or content expertise.”  

It’s also been a long-standing AHRQ policy not to disclose the names of advisors or authors until its reports are finalized.

“This policy is aimed at helping the authors maintain their independence by not being subject to lobbying by industry reps or others with conflicts of interest, either financial or intellectual,” AHRQ spokesman Bruce Seeman explained in an email.

But others wonder if the policy damages the agency’s reputation and the credibility of its research, by not giving the public a chance to review and comment on possible biases before a final report is released. The American Medical Association urged the AHRQ to change its policy last year.

“We would suggest that AHRQ publish the list of all those involved in any aspect of the report during the comment period to help remove any perception of potential conflict,” Dr. James Madara, the AMA’s Executive Director and CEO, wrote in a letter to the agency last year.

CDC Guideline Update

It might be tempting to dismiss the work of an obscure federal agency that produces wonky reports that are mostly read by public health researchers and government bureaucrats. That would be a mistake. It was a 2014 AHRQ report on opioids – co-authored by Chou – that played a foundational role in the CDC guideline.

Although the CDC guideline is voluntary and only intended for primary care physicians treating chronic pain, it has become mandatory policy for doctors in all specialties, as well as other federal agencies, dozens of states, insurers, pharmacy chains and law enforcement agencies. In effect, the guideline has delivered on the goals sought by Kolodny, Von Korff and Chou in 2011. The standard of care in pain management is no longer determined by pain specialists.

Chou and his colleagues hope the new AHRQ report will have a similar impact, not just in government, but throughout the healthcare system.

“The information in this report is intended to help healthcare decision makers — patients and clinicians, health system leaders, and policymakers, among others — make well-informed decisions and thereby improve the quality of healthcare services,” they said.

In addition to its report on opioid treatments for chronic pain, AHRQ has also finalized studies on the effectiveness of Nonopioid Medications for Chronic Pain and Nonpharmacologic Treatments for Chronic Pain, such as acupuncture and meditation.

All three reports will be utilized by the CDC as it prepares an update and expansion of its opioid guideline, which is expected in late 2021.  That effort is being overseen by the Board of Scientific Counselors at the CDC’s Center for Injury Prevention & Control.  Roger Chou happens to be one of its members.  

How CDC Bungled Early Coronavirus Testing

By Rachana Pradhan, Kaiser Health News

As the novel coronavirus snaked its way across the globe, the Centers for Disease Control and Prevention in early February distributed 200 test kits it had produced to more than 100 public health labs run by states and counties nationwide.

Each kit contained material to test a mere 300 to 400 patients. And labs, whether serving the population of New York City or tiny towns in rural America, apparently received the same kits.

The kits were distributed roughly equally to locales in all 50 states. That decision presaged weeks of chaos, in which the availability of COVID-19 tests seemed oddly out of sync with where testing was needed.

A woman in South Dakota with mild symptoms and no fever readily got the test and the results. Meanwhile, political leaders and public officials in places like New York, Boston, Seattle and the San Francisco Bay Area — all in the throes of serious outbreaks ― couldn’t get enough tests to screen ill patients or, thereby, the information they needed to protect the general public and stem the outbreak of the virus, whose symptoms mimic those of common respiratory illnesses.

Rapid testing is crucial in the early stages of an outbreak. It allows health workers and families to identify and focus on treating those infected and isolate them.

Yet health officials in New York City and such states as New York, Washington, Pennsylvania and Georgia confirmed to Kaiser Health News that they each initially got one test kit, calling into question whether they would have even stood a chance to contain the outbreaks that would emerge. They would soon discover that the tests they did receive were flawed, lacking critical components and delivering faulty results.

During those early weeks, the virus took off, infecting thousands of people and leading to nationwide social distancing and sheltering in place. Public health officials are just beginning to grapple with the fallout from that early bungling of testing, which is likely to haunt the country in the months to come.

Too Little Too Late

The first shipment to Washington state arrived more than two weeks after officials there announced the first U.S. case of coronavirus, and at a moment when deadly outbreaks of the disease were already festering in places like the Life Care Center in Kirkland. Within weeks, three dozen people infected with COVID-19 would die at the nursing home in the suburbs of Seattle.

The spread of COVID19 would not take long to overwhelm the state, which has over 2,200 people infected.

The Trump administration in recent days has attempted to speed testing for the virus after early missteps hampered the government’s response to contain the contagion, and officials have had to respond to a barrage of criticism from public health experts, state officials and members of Congress.

Federal health officials have eased the process for university and commercial labs to perform their own tests, and they are ramping up their capacity. As of March 16, public and private labs in the U.S. had the ability to test more than 36,000 people a day, according to estimates compiled by the American Enterprise Institute, a conservative-leaning think tank in Washington, D.C., a figure expected to rapidly escalate in coming weeks. That figure, however, can vary considerably by state and does not indicate how many tests are actually given to patients.

“We are now beginning to see that they have spread out in a prioritized way. We asked them to prioritize the regions that were mostly affected,” Deborah Birx, the coronavirus response coordinator for the White House Coronavirus Task Force, said Wednesday of private labs’ testing, without elaboration.

The scaling up of testing is set to take place after weeks of faltering and hundreds, if not thousands, of undiagnosed people spreading the virus. For example, New York’s state health department received a faulty CDC test kit on Feb. 8 for 800 patient specimens, an amount that’s consistent with other states, according to a spokesperson. It later began testing patients with a test that state officials developed based on the CDC protocol and has significantly increased testing.

In New York City, the first batch was obtained on Feb. 7.

“The other state and local public health laboratories got test kits as they became available,” said Eric Blank, chief program officer of the Association of Public Health Laboratories.

Places in the middle of the country with no outbreaks had the luxury of time to plan. For example, Missouri officials have had about 800 tests to work with, leading to only 395 performed so far in the region by public health labs ― 26 of which were positive. When private lab tests are accounted for, as of Friday there were 47 confirmed cases.

Health care providers and public health staff in the state, however, benefited from the fact that there is less international travel to the region, according to infectious disease expert Dr. Steven Lawrence of Washington University in St. Louis.

“This is very similar to 1918 with the influenza pandemic — St. Louis had more time to prepare and was able to put measures in place to flatten the curve than, say, Philadelphia,” Lawrence said. “Seattle didn’t have an opportunity to prepare as much in advance.”

While commercial labs are coming online, strict restrictions are limiting testing capabilities, Lawrence said.

“The state has had their hands tied,” he added.

Waiting and Wondering

Because of a widespread lag in testing, it is still a mystery for thousands of people to know whether they’ve come into contact with an infected person until well after it happens.

“CDC will distribute tests based on where they can do the most good. But without hospital-based testing and commercial testing, it will not be possible to meet the need,” said Tom Frieden, who led the CDC during the Obama administration and is a former commissioner of the New York City Health Department.

Since the CDC’s initial distribution, states have been reordering more tests through the office’s International Reagent Resource ― a long-standing tool that public health labs have relied on. They have also revised testing protocols to use only one sample per person, which boosts the number of people screened.

Yet problems still abound with tests or other materials needed to be able to detect the virus. California Gov. Gavin Newsom said on March 12 that county public health labs can’t use all of the 8,000 test kits the state has because they are missing key components.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation, which is not affiliated with Kaiser Permanente.

Do Smartphones Cause More Headaches?

By Pat Anson, PNN Editor

People with headaches who use smartphones are more likely to use more pain medication, but get less relief from the drugs, according to a new study conducted in India.

Researchers surveyed 400 people who suffer from a primary headache condition, which includes migraine, tension headache and other types of headaches, asking them about their smartphone and medication use.

The smartphone users were more likely to take pain-relieving drugs for their headaches than non-users, with 96% of smartphone users taking the drugs compared to 81% of non-users. Smartphone users took an average of eight pills per month compared to five pills per month for non-users.

Smartphone users also reported less relief from pain medication, with 84% gaining moderate or complete relief of headache pain compared to 94% of non-users. The study findings were published in the journal Neurology Clinical Practice.

"While these results need to be confirmed with larger and more rigorous studies, the findings are concerning, as smartphone use is growing rapidly and has been linked to a number of symptoms, with headache being the most common," said lead author Deepti Vibha, DM, of All India Institute of Medical Sciences.

The study has limitations. It only examined people at one point in time and did not follow them over an extended period. It also relied on people to self-report their symptoms and use of pain medication.

While the study does not prove that smartphone use causes headaches or greater use of pain medication, it does show an association.

“There is a great deal of speculation among the lay population regarding the effect of computers and mobile phones on ailments such as headaches and neck pain. However, although there are anecdotal stories suggesting a link between technology use and pain, there is little evidence of either a definitive relationship or data absolving mobile phones or computers from a link to recurrent pain,” wrote Heidi Moawad, MD, of Case Western Reserve University, in an editorial accompanying the study.

“Smartphone users may rely on the devices for many hours per day -- while on the go, resting, or working -- which puts a strain on the eyes, neck, and back. As people are becoming more dependent on these devices, it would be worthwhile to know whether using smartphones could lead to health problems.”

A 2017 study speculated that high energy visible (HEV) light – also known as blue light – emitted by smartphones, laptops, desktop computers and other digital devices could contribute to headaches by causing eye strain. Blue light has a very short wavelength that penetrates deep into the eye.

A nationwide survey of nearly 10,000 adults by The Vision Council found that about a third had symptoms of digital eye strain, including neck and shoulder pain, headache, blurred vision and dry eyes.

More information about blue light can be found at BlueLightExposed.com.