Placebo Effect is All in Our Heads

By Pat Anson, Editor

A new study has given researchers a better understanding why some people given a simple sugar pill will say it significantly reduces their pain.

It’s all in their heads.

Using functional magnetic resonance brain imaging (fMRI), scientists at the Northwestern Medicine and the Rehabilitation Institute of Chicago (RIC) have identified for the first time the region of the brain that's responsible for the "placebo effect" in pain relief. It’s an area in the front part of the brain -- called the mid frontal gyrus -- that also plays a key role in our emotions and decision making.

In two clinical trials involving 95 patients with chronic pain from osteoarthritis, researchers found that about half of the participants had mid frontal gyrus that had more connectivity with other parts of the brain and were more likely to respond to the placebo effect.

The use of fMRI images to identify these “placebo responders” and eliminate them from clinical trials could make future research far more reliable. It could also lead to more targeted pain therapy based on a patient’s brain images, instead of a trial-and-error approach that exposes patients to ineffective and sometimes dangerous medications.

"Given the enormous societal toll of chronic pain, being able to predict placebo responders in a chronic pain population could both help the design of personalized medicine and enhance the success of clinical trials," said Marwan Baliki, PhD,  a research scientist at RIC and an assistant professor of physical medicine and rehabilitation at Northwestern University Feinberg School of Medicine.

“This can help us better conduct clinical studies by screening out patients that respond to placebo and we can just include patients that do not respond. And we can measure the efficacy of a certain drug in a much more effective manner.”

Baliki told Pain News Network that differences in the brain could explain why some prescription drugs – such as Lyrica (pregabalin) – are effective in giving pain relief to some patients, but not for others.

“If we do the same with Lyrica, maybe we can find another area of the brain that can predict the response to that drug,” he said.

The study findings are being published in PLOS Biology.

"The new technology will allow physicians to see what part of the brain is activated during an individual's pain and choose the specific drug to target this spot," said Vania Apkarian, a professor of physiology at Feinberg and study co-author. "It also will provide more evidence-based measurements. Physicians will be able to measure how the patient's pain region is affected by the drug."

Currently, most clinical studies involving pain are conducted on healthy subjects in controlled experimental settings. Those experiments usually induce acute pain through immersion in cold water, pressure or some other type of applied pain. Baliki says there are significant differences between acute and chronic pain, and the experiments often translate poorly in clinical settings where pain is usually chronic.   

Researchers Discover ‘Brain Signature’ for Fibromyalgia

By Pat Anson, Editor

Researchers at the University of Colorado Boulder have discovered a “brain signature” that identifies fibromyalgia with 93 percent accuracy, a potential breakthrough in the diagnosis and treatment of a chronic pain condition that five million Americans suffer from.

Fibromyalgia is a poorly understood disorder characterized by deep tissue pain, headaches, fatigue, anxiety, depression and insomnia. The cause of fibromyalgia is unknown and there is no universally accepted way to diagnose or treat it.

The CU Boulder researchers used MRI scans to study brain activity in a group of 37 fibromyalgia patients and 35 control patients, who were exposed to a series of painful and non-painful sensations.

The researchers were able to identify three neurological patterns in the brain that correlated with the pain hypersensitivity typically experienced with fibromyalgia.

UNIVERSITY OF COLORADO BOULDER

"The potential for brain measures like the ones we developed here is that they can tell us something about the particular brain abnormalities that drive an individual's suffering. That can help us both recognize fibromyalgia for what it is - a disorder of the central nervous system - and treat it more effectively," said Tor Wager, director of CU Boulder’s Cognitive and Affective Control Laboratory.

If replicated in future studies, the findings could lead to a new method to diagnosis fibromyalgia with MRI brain scans. Patients who suffer from fibromyalgia have long complained that they are not taken seriously and have to visit multiple doctors to get a diagnosis.

"The novelty of this study is that it provides potential neuroimaging-based tools that can be used with new patients to inform about the degree of certain neural pathology underlying their pain symptoms," said Marina López-Solà, a post-doctoral researcher at CU Boulder and lead author of a study published in the journal Pain. "This is a helpful first step that builds off of other important previous work and is a natural step in the evolution of our understanding of fibromyalgia as a brain disorder."

One patient advocate calls the use of MRI brain scans a breakthrough in fibromyalgia research.

"New cutting-edge neurological imaging used by CU Boulder researchers advances fibromyalgia research by light years," said Jan Chambers, founder of the National Fibromyalgia & Chronic Pain Association. "It allows scientists to see in real time what is happening in the brains of people with fibromyalgia. 

"In fibromyalgia, the misfiring and irregular engagement of different parts of the brain to process normal sensory stimuli like light, sound, pressure, temperature and odor, results in pain, flu-like sensations or other symptoms.  Research also shows that irregular activity in the peripheral nervous system may be ramping up the central nervous system (brain and spinal cord).  So the effect is like a loop of maladjustment going back and forth while the brain is trying to find a balance.  This extra brain work can be exhausting." 

The theory that fibromyalgia is a neurological disorder in the brain is not accepted by all. Other experts contend it is an autoimmune disorder or even a “symptom cluster” caused by multiple chronic pain conditions. And some doctors still refuse to accept fibromyalgia as a disease.

One company has already developed a diagnostic test for fibromyalgia – and it’s not a brain scan. EpicGenetics has a blood test that looks for protein molecules produced by white blood cells. Fibromyalgia patients have fewer of these molecules than healthy people and have weaker immune systems, according to the founder of EpicGenetics. But critics have called the blood test “junk science” that is backed up by little research.

Wheat Protein Could Worsen Chronic Illness

By Pat Anson, Editor

Gluten isn’t the only reason why some people should avoid eating wheat.

German researchers have discovered a second protein in wheat that triggers inflammation and worsen symptoms of multiple sclerosis, lupus, rheumatoid arthritis and other chronic illnesses. The finding could help explain why some people who are not gluten intolerant and do not have celiac disease still benefit from going on a gluten-free diet.

Researchers say a family of proteins called amylase-trypsin inhibitors (ATIs) make up only about 4% of the protein found in wheat. But they can trigger powerful immune system reactions outside the digestive system, in the lymph nodes, kidneys, spleen and brain.

"As well as contributing to the development of bowel-related inflammatory conditions, we believe that ATIs can promote inflammation of other immune-related chronic conditions outside of the bowel,” said lead researcher, Professor Detlef Schuppan of Johannes Gutenberg University.

“The type of gut inflammation seen in non-celiac gluten sensitivity differs from that caused by celiac disease, and we do not believe that this is triggered by gluten proteins. Instead, we demonstrated that ATIs from wheat, that are also contaminating commercial gluten, activate specific types of immune cells in the gut and other tissues, thereby potentially worsening the symptoms of pre-existing inflammatory illnesses.”

Schuppan presented his findings at United European Gastroenterology Week. He said future clinical studies will explore the role that ATIs play on chronic health conditions in more detail.

"We are hoping that this research can lead us towards being able to recommend an ATI-free diet to help treat a variety of potentially serious immunological disorders," said Schuppan.

Celiac disease is a gastrointestinal inflammation caused by the ingestion of wheat, barley, rye, and other foods containing gluten. About 1-2% of the population has celiac disease, but most cases go undiagnosed and untreated.

People with non-celiac gluten sensitivity (NCGS) may also develop gastrointestinal symptoms, as well as headaches, chronic fatigue, fibromyalgia and allergies. Abdominal pain and irregular bowel movements are frequently reported with NCGS, which can make it difficult to distinguish from irritable bowel syndrome (IBS).

The symptoms typically appear after the consumption of gluten-containing food and improve rapidly on a gluten-free diet, even though gluten does not appear to cause the condition. Schuppan says the real culprit may be ATIs.

"Rather than non-celiac gluten sensitivity, which implies that gluten solitarily causes the inflammation, a more precise name for the disease should be considered," he said.

The Importance of Participating in Pain Research

By Barby Ingle, Columnist

Over the years I have participated in many research studies and potential new treatments. One such study was just published in the Journal of Translational Medicine by Drs. Garabed G. Demerjian, Andre Barkhordarian and Francesco Chiappelli.

So many people over the years meet me and soon realize that I have a device called an oral orthotic in my mouth. This “OO” as I lovingly call it has helped me so much, and now there is published research behind what it is doing for me.

Back in 2002 when I developed Reflex Sympathetic Dystrophy, I lost partial vision in my right eye. I saw many eye doctors and ENT (ear, nose and throat) specialists who were unable to pinpoint where the breakdown in the nerves were. They hypothesized that it was due to inflammation from the RSD cutting off a nerve pathway.

Within 30 seconds of putting in the OO, I had my vision back after 10 years of being told that I would never see properly again. My world is now brighter with the OO, literally.

I also had improvement in pain levels affecting my entire body. I have been able to get my infusion therapy minimized to only 1 or 2 boosters a year and get off all daily pain medication. I also have had improvement in my balance, coordination, dystonia, memory and mood. My migraines and headaches are less frequent, and although weather and pressure changes still affect me, it is not to the extent it was prior to my oral orthotic use.

The research doctors and my treating doctor, Garabed Demerjian, approached their study with an individualized approach that they made measurable for each patient who participated. I underwent multiple MRIs, cat-scans, X-rays, synovial fluid testing, psychological testing, and saliva testing.

These tests were done in an effort to quantify the outcome and show the effectiveness of the oral orthotic. I participated in the study in 2015, about three years after getting my OO. I already knew that the tests were going to show amazing results. That is great for the scientific community and for advancing new treatment options.

Traditional research in the health sciences usually involves control and experimental groups of patients, and descriptive and statistical measurements obtained from samples in each group. The research I was part of used a novel model known as translational medicine, which "translates" research into more effective healthcare -- a "bench-to-bedside" approach. This type of research is increasingly becoming more established in modern contemporary medicine.

I often say that each patient is different. Our biological makeup and life experiences mean disease often affects us in different ways – making a one-size-fits-all approach to medicine impractical. Science is seeing this too. It’s becoming more focused on translational research for the ultimate benefit of each individual patient. This is what we need.

I know and understand that being part of a research study is not for everyone. It doesn’t always go as great as it did for me. But stepping up and trying something that can benefit others is very rewarding.

I thank all of the research doctors and scientists who are making a difference in our lives. It can take years of research before they see actual results, and they are not always recognized for their efforts. I find it hard to express the full gratitude they deserve. Thank you to our researchers in the chronic pain community.

Barby Ingle suffers from Reflex Sympathetic Dystrophy (RSD) and endometriosis. Barby is a chronic pain educator, patient advocate, and president of the International Pain Foundation. She is also a motivational speaker and best-selling author on pain topics.

More information about Barby can be found on her website.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

Negative Thoughts About Sleep Make Pain Worse

By Pat Anson, Editor

Negative thoughts about pain and not being able to sleep can worsen chronic pain conditions like fibromyalgia, arthritis and back pain, according to British researchers.

“Pain-related sleep beliefs appear to be an integral part of chronic pain patients' insomnia experience,” said Nicole Tang, a psychologist in the Sleep and Pain Laboratory at the University of Warwick. "Thoughts can have a direct and/or indirect impact on our emotion, behaviour and even physiology. The way how we think about sleep and its interaction with pain can influence the way how we cope with pain and manage sleeplessness.”

Tang and her colleagues developed a scale to measure beliefs about sleep and pain in chronic pain patients, along with the quality of their sleep.

The scale was tested on four groups of patients suffering from long-term pain and bad sleeping patterns, and found to be a reliable predictor of future pain and insomnia.

"This scale provides a useful clinical tool to assess and monitor treatment progress during these therapies," said Esther Afolalu, a graduate student and researcher at the University of Warwick. 

university of warwick

"Current psychological treatments for chronic pain have mostly focused on pain management and a lesser emphasis on sleep but there is a recent interest in developing therapies to tackle both pain and sleep problems simultaneously."

Researchers found that people who believe they won't be able to sleep because of their pain are more likely to suffer from insomnia, thus causing more pain. The vicious cycle of pain and sleeping problems was significantly reduced after patients received instructions in cognitive-behavioural therapy (CBT), a form of psychotherapy in which a therapist works with a patient to reduce unhelpful thinking and behavior.

The study, published in the Journal of Clinical Sleep Medicine, is not the first to explore the connection between pain and poor sleep.

A 2015 study published in the journal PAIN linked insomnia and impaired sleep to reduced pain tolerance in a large sample of over 10,000 adults in Norway. Those who had trouble sleeping at least once a week had a 52% lower pain tolerance, while those who reported insomnia once a month had a 24% lower tolerance for pain.

Study Finds Link Between Weather and Chronic Pain

By Pat Anson, Editor

There may be something to the old adage about “feeling under the weather.”

Early results from a smartphone-based weather study in the UK show that rain and lack of sunshine have an impact on how we perceive pain.

Over 9,000 people are participating in The University of Manchester’s Cloudy with a Chance of Pain project,  using a special app to record their daily pain levels.  

The app also captures hourly weather conditions using the phone’s GPS, giving researchers the ability to compare the pain data with real-time local weather.

Researchers reviewed data from participants in three cities – Leeds, Norwich and London – and found that as the number of sunny days increased from February to April, the amount of time participants spent in severe pain decreased.

Conversely, when the weather turned rainy and cloudy in June, the amount of time spent in severe pain increased.

The 18-month study is only half complete and researchers are still looking to recruit as many people as possible who are willing to track their symptoms.

“If you are affected by chronic pain, this is your chance to take do something personally – and easily – to lead to a breakthrough in our understanding of pain,” said lead investigator Will Dixon, a professor of Digital Epidemiology at The University of Manchester’s School of Biological Sciences.

The Greek philosopher Hippocrates in 400 B.C was one of the first to note that changes in the weather can affect pain levels. Although a large body of folklore has reinforced the belief that there is a link between weather and pain, the science behind it is mixed.

A 2014 study in Australia found that low back pain is not associated with temperature, humidity and rain.  A 2013 Dutch study also concluded that weather has no impact on fibromyalgia symptoms in women.

“Once the link is proven, people will have the confidence to plan their activities in accordance with the weather. In addition, understanding how weather influences pain will allow medical researchers to explore new pain interventions and treatments,” says Dixon.

People with arthritis or chronic pain who are interested in joining the Cloudy with a Chance of Pain project – and who have access to a smartphone – can download the app by clicking here. You need to be at least 17 and live in the UK.

Participants are encouraged to record their pain symptoms daily until the project ends in January.  Researchers hope to use data to develop “pain forecasts” based on weather predictions.

Study Finds Link Between Chronic Pain and Anxiety

By Pat Anson, Editor

A new study helps explain why so many chronic pain patients also suffer from anxiety or depression.

Researchers at the University of Vermont discovered that the body releases the same neurotransmitter in response to stress as it does to chronic neuropathic pain. The findings, published in the journal Biological Psychiatry, could lead to the development of a new and safer class of medication that could treat both pain and anxiety.

In studies on laboratory mice, researchers found that pain signals and the PACAP neurotransmitter (pituitary adenylate cyclase activating polypeptide) share the same pathway to the brain - the spino-parabrachiomygdaloid tract - which travels from the spinal cord to the amygdala, where the brain processes emotional behavior.

"Chronic pain and anxiety-related disorders frequently go hand-in-hand," says senior author Victor May, PhD, a professor of neurological sciences at the University of Vermont. "By targeting this regulator and pathway, we have opportunities to block both chronic pain and anxiety disorders."

May and his colleagues found that anxious behavior and pain hypersensitivity were significantly reduced when a PACAP receptor antagonist -- designed to block the release of the neurotransmitter -- was applied.

"This would be a completely different approach to using benzodiazepine and opioids - it's another tool in the arsenal to battle chronic pain and stress-related behavioral disorders," said May, who found in a previous study that PACAP was highly expressed in women exhibiting symptoms of post-traumatic stress disorder (PTSD).

May’s findings are important because anxiety and stress are currently treated with sedatives, benzodiazepines and other central nervous system (CNS) depressants. When taken with opioid pain medication, the combination of the drugs can lead to extreme sleepiness, respiratory depression, coma and death.

Yesterday, the U.S. Food and Drug Administration ordered new “black box” warning labels be put on all medications that contain opioids, benzodiazepines and CNS depressants, warning patients and physicians about the increased risk.

According to a 2015 study, over a third of the patients prescribed opioids for chronic musculoskeletal pain were given a sedative. And patients with a history of psychiatric and substance abuse disorders were even more likely to be co-prescribed opioids and sedatives.

Animal Studies Show Promise for Safer Opioids

By Pat Anson, Editor

Animal studies currently underway could hold the key to developing new opioid therapies that relieve pain without the risk of addiction, overdose and other harmful side effects.

Researchers at Wake Forest Baptist Medical Center in North Carolina have developed a pain killing compound -- called BU08028 – that relieves pain in monkeys without causing physical dependence. BU08028 is similar to buprenorphine, an opioid currently used to treat both pain and addiction.

"Based on our research, this compound has almost zero abuse potential and provides safe and effective pain relief," said Mei-Chuan Ko, Ph.D., professor of physiology and pharmacology at Wake Forest Baptist and lead author of the study published in the Proceedings of the National Academy of Sciences.

"This is a breakthrough for opioid medicinal chemistry that we hope in the future will translate into new and safer, non-addictive pain medications."

This study, which was conducted on 12 monkeys, targeted a combination of mu opioid receptors in the brain – the same receptors targeted in humans by existing opioid pain medication.

The Wake Forest researchers examined behavioral, physiological and pharmacologic factors and found that BU08028 blocked pain signals without the side effects of respiratory depression, itching or adverse cardiovascular events. In addition, the study showed pain relief lasted up to 30 hours in the monkeys and repeated administration did not appear to cause physical dependence.

"To our knowledge, this is the only opioid-related analgesic with such a long duration of action in non-human primates," said Ko. “Given the decades-long effort aimed at developing abuse-free opioid analgesics, BU08028 represents a major breakthrough for opioid medicinal chemistry.”

Ko plans further animal studies on related compounds to see if they have the same safety profiles as BU08028. If those studies are successful, he hopes to begin studies on humans with the ultimate goal of getting FDA approval for a new class of opioid medication.

The research is funded by the National Institutes of Health and National Institute on Drug Abuse.

Rat Study Targets Peripheral Nerves

Another animal study is taking a different approach to pain relief – by targeting nerves in peripheral tissue – not the mu opioid receptors in the brain and spinal cord.

In findings published in Cell Reports, researchers at the University of Texas found that targeting delta opioid receptors on sensory neurons in the peripheral tissue of laboratory rats produces fewer side effects and with much lower abuse potential.

"Being able to increase the responsiveness of peripheral opioid receptor systems could lead to a reduction in systemic opioid administration, thereby reducing the incidence of side effects," says senior study author Nathaniel Jeske of the University of Texas Health Science Center at San Antonio.

One complication is that delta opioid receptors in peripheral tissues only become activated in the presence of inflammation. Because it has not been clear how to overcome this need for an inflammation trigger, the development of drugs that target peripheral nerves has been limited.

Jeske and his colleagues discovered a protein called GRK2 that binds to and prevents delta opioid receptors on rat sensory neurons from responding normally to opioids. But when those peripheral nerves were exposed to a natural inflammatory molecule called bradykinin, GRK2 moved away from the delta opioid receptors, setting off a biochemical reaction that restored the functioning of these receptors.

In addition, rats with reduced GRK2 levels in peripheral sensory neurons regained sensitivity to the pain-relieving effects of a drug that activates delta opioid receptors, and without the need for an inflammatory trigger.

The researchers hope to replicate the same findings using human tissues.

"By shedding light on how inflammation activates delta opioid receptors, this research could potentially lead to the development of safer, more effective opioids for the treatment of pain," said Jeske, whose work is funded by the National Institutes of Health.

Do Men Get More Pain Relief From Marijuana?

By Pat Anson, Editor

Experts tell us that women are more likely to experience chronic pain than men, feel pain more intensely, and are more likely to be undertreated for pain than men are.

The gender gap in pain grew a little wider this week with a new study, published in Drug and Alcohol Dependence, which claims women get far less pain relief from smoking marijuana than men do.

"These findings come at a time when more people, including women, are turning to the use of medical cannabis for pain relief," said lead author Ziva Cooper, PhD, associate professor of clinical neurobiology at Columbia University Medical Center. "Preclinical evidence has suggested that the experience of pain relief from cannabis-related products may vary between sexes, but no studies have been done to see if this is true in humans."

Cooper and her colleagues conducted two double-blinded, placebo-controlled studies that looked at the analgesic effects of cannabis in 42 healthy recreational marijuana smokers – half of them men and half women.

All smoked marijuana at least four times a week prior to enrolling in the study. Participants were excluded if they had pain.

After smoking the same amount of cannabis or a placebo, the participants immersed one hand in a cold-water bath until the pain could no longer be tolerated. Following the immersion, the participants answered a short pain questionnaire.

Among those who smoked cannabis, men reported a significant decrease in pain sensitivity and an increase in pain tolerance. But the women who smoked cannabis did not experience a significant decrease in pain sensitivity, although they did report a small increase in pain tolerance shortly after smoking.

No gender differences were found in how intoxicated the participants felt or how much they liked the effect of cannabis.

“These results indicate that in cannabis smokers, men exhibit greater cannabis-induced analgesia relative to women,” said Cooper.  “Sex-dependent differences in cannabis’s analgesic effects are an important consideration that warrants further investigation when considering the potential therapeutic effects of cannabinoids for pain relief.”

A marijuana advocate and caregiver for patients in Rhode Island said she was shocked by the study findings.

"This study concerns me that some women will read this and not even try the most magical pain relief out there," said Ellen Lenox Smith, a columnist for Pain News Network. "We have never, in the nine years of growing for myself and as caregivers for patients, ever had a time that this was not successful because of one's sex. We have had equal amounts of men and women and the only person that did not have success was an elderly woman that was not able to follow the directions due to her anxiety of using it. That was due to the stigma from society, not the product."

Do women really respond differently to marijuana or is there a flaw in the study itself?

Previous research has found that women respond differently to the cold water test and have far less tolerance for pain induced by cold water immersion than men.

“Most studies have used some form of the cold pressor test in which subjects immerse their arm or hand in circulating cold water for a defined period of time, and their results support the hypothesis that cold pain sensitivity is more pronounced in females,” researchers reported in a 2009 review of nearly two dozen studies that used the cold water test.  “Based on the present set of studies, it appears that sex differences in cold pain are consistent, particularly for suprathreshold measures such as tolerance and pain ratings.”

The Columbia University study was funded by the U.S. National Institute on Drug Abuse. Ziva Cooper also received salary support from Insys Therapeutics, which is developing cannabis-based drugs.

‘Weird and Cool’ Discovery Could Lead to Safer Opioid

By Pat Anson, Editor

A “weird and cool” discovery by a team of international researchers could lead to the development of a new opioid medication that relieves pain without the risk of abuse and overdose.

In a case of reverse engineering, scientists in the U.S. and Germany deciphered the atomic structure of the brain’s mu-opioid receptor and then designed a drug – called PZM21 – that activates the receptor without the typical side effects of opioids. In experiments on mice, PZM21 did not cause drug-seeking behavior and did not interfere with breathing – the main cause of death in opioid overdoses.

“With traditional forms of drug discovery, you’re locked into a little chemical box,” said Brian Shoichet, PhD, a professor of pharmaceutical chemistry at UC San Francisco’s School of Pharmacy.

“But when you start with the structure of the receptor you want to target, you can throw all those constraints away. You’re empowered to imagine all sorts of things that you couldn’t even think about before.”

Shoichet and colleagues at Stanford University, the University of North Carolina and the Friedrich Alexander University in Erlangen, Germany published their findings in the journal Nature.

"This promising drug candidate was identified through an intensively cross-disciplinary, cross-continental combination of computer-based drug screening, medicinal chemistry, intuition and extensive preclinical testing," said Brian Kobilka, MD, a Nobel Prize winner and professor of molecular and cellular physiology at Stanford. It was Kobilka who first established the molecular structure of the opioid receptor.

Shoichet and his research team conducted roughly four trillion “virtual experiments” on UCSF computers, simulating how millions of different drug candidates could turn and twist in millions of different angles – called “molecular docking” -- to see how they fit into a pocket on the receptor and activate it. They avoided using molecules linked to the respiratory suppression and constipation typical of other opioids.

This led to the development of PZM21, which efficiently blocked pain in mice without producing the constipation and breathing suppression typical of other opioids. PZM21 also appears to dull pain by affecting opioid circuits in the brain only, with little effect on opioid receptors in the spinal cord. No other opioid has that effect, which Shoichet says is “unprecedented, weird and cool.”

The drug also didn’t produce the hyperactivity that other opioids trigger in mice by activating the brain’s dopamine systems. The mice did not display drug-seeking behavior by spending more time in chambers where they had previously received doses of PZM21.

“After we replicated the lab experiments and mouse studies several times, then I became excited about the potential of this new drug,” said Bryan Roth, MD, a professor of pharmacology and medicinal chemistry at University of North Carolina.

Researchers say more work is needed to establish that PZM21 is truly non-addictive, and to confirm that it is safe and effective in humans.

 “We haven’t shown this is truly non-addictive,” Shoichet cautioned. “At this point we’ve just shown that mice don’t appear motivated to seek out the drug.”

Is Chronic Pain a Family Affair?

By Pat Anson, Editor

We can credit – or blame – our parents for many things, including our eye color, hair color, height, weight, personality, even our cravings for certain foods.

And if our parents have chronic pain, we are also more likely to suffer from pain ourselves, according to research recently published in the journal Pain. 

“Offspring of parents with chronic pain are at increased risk for pain and adverse mental and physical health outcomes,” wrote co-authors Amanda Stone of Vanderbilt University and Anna Wilson of Oregon Health & Science University.

"Although the association between chronic pain in parents and offspring has been established, few studies have addressed why or how this relation occurs."

Stone and Wilson developed a “conceptual model” of how chronic pain can be transmitted from parent to child through genes, parenting, stress, and lifestyle choices.

"Such a framework highlights chronic pain as inherently familial and intergenerational, opening up avenues for new models of intervention and prevention that can be family-centered and include at-risk children," they wrote.

The researchers identify five "plausible mechanisms" to explain the transmission of chronic pain from parent to child:

• Genetics. Children of parents with chronic pain might be at increased genetic risk for sensory as well as psychological components of pain. Research suggests that genetic factors account for about half of the risk of chronic pain in adults.
• Early Neurobiological Development. Having a parent with chronic pain may affect the functioning of the nervous system during critical periods of child development. For example, a baby's development might be affected by the mother's stress levels or behavior during and after pregnancy.
• Social Learning. Children may learn "maladaptive pain behaviors" from parents, such as catastrophizing and excessive worrying about pain.
• Parenting and Health Habits. Chronic pain risk could be affected by parenting behaviors linked to adverse child outcomes--for example, permissive parenting or lack of consistency and warmth. The parents' physical activity level and other health habits might also play a role.
• Exposure to Stress. There may be adverse effects from growing up in stressful circumstances related to chronic pain -- for example, financial problems or parents' inability to perform daily tasks.

Other factors that may explain why some children are at greater risk include chronic pain in both parents, the location of the parent's pain, and the children's personal temperament.

"The outlined mechanisms, moderators, and vulnerabilities likely interact over time to influence the development of chronic pain and related outcomes," wrote Stone and Wilson, who hope their model will help guide future research toward developing early prevention and treatment approaches for children at risk of chronic pain.

Poor Fitness Leads to Childhood Pain

Another recent study in Finland found that poor physical fitness and sedentary behavior are linked to pain in children as young as 6-8 years of age.

The Physical Activity and Nutrition in Children (PANIC) study at the University of Eastern Finland analyzed the physical fitness, exercise, hobbies, body fat and various pain conditions in 439 children. Physically unfit children suffered from headaches more frequently than others. High amounts of screen time and other sedentary behavior were also associated with increased prevalence of pain conditions.

“Pain experienced in childhood and adolescence often persists later in life. This is why it is important to prevent chronic pain, recognize the related risk factors and address them early on. Physical fitness in childhood and introducing pause exercises to the hobbies of physically passive children could prevent the development of pain conditions,” the study found.

Doctors Warn of Crisis in Osteoporosis Treatment

By Pat Anson, Editor

Thirty years of progress in treating osteoporosis and reducing bone fractures in the elderly is rapidly being reversed, according to two bone health experts.

In an article called A Crisis in the Treatment of Osteoporosis, published in the Journal of Bone and Mineral Research, Sundeep Khosla, MD, and Elizabeth Shane, MD, say too many patients at high risk of fractures are not being diagnosed or treated for osteoporosis, even though hormones and bisphosphonate drugs are available to help strengthen their bones.

“The field of osteoporosis may be coming full circle, and that is not good for the millions of older women and men who will suffer painful and disabling spine and hip fractures - fractures that might have been prevented,” Khosla and Shane wrote.

“As physicians, we are now watching as the fundamental progress made to reduce fractures and dramatically improve the quality of life of our patients during the past 30 years unravels.”

More than 10 million Americans suffer from osteoporosis and 44 million have its precursor, a loss in bone density that raises the risk of fractures and disability.  Breaking a bone in your spine or hip may be so traumatic – especially for the elderly -- that it doubles your chances of developing chronic widespread body pain.

Bisphosphonates such as Fosamax have been found to be effective at slowing the loss of bone mass and reducing fractures, but concerns about their use rose when patients reported side effects such as joint and musculoskeletal pain. That made some patients reluctant to take bisphosphonates and doctors less likely to prescribe them.  

Khosla and Shane cite a recent study that found only 3 percent of patients with a hip fracture in 2013 were given bisphosphonates to strengthen their bones, down from 15% of patients in 2004.

“In short, we, as physicians who care deeply about the treatment of patients with osteoporosis, find ourselves in a dire situation. At a point in time when we have developed pharmacologic tools capable of preventing enormous suffering and needless mortality, we may well be coming back full circle: the downward spiral of vertebral fracture, hip fracture, immobility, loss of independence, and premature death that we thought we had conquered may soon become the accepted norm again,” they wrote. 

“There can be no more urgent call to action for our field than we face today. We must find ways to ensure that patients who need appropriate treatment for osteoporosis are not only prescribed effective medications, but are also equipped with the information they need to make an informed choice on taking these medications.”

Khosla is an endocrinologist, research scientist, professor of medicine and director of the Clinical and Translational Science Award Program at the Mayo Clinic in Rochester, Minnesota. Shane is an endocrinologist, research scientist, professor of medicine and vice chair for clinical and epidemiological research at Columbia University in New York.

A quarter-million Americans sustain a hip fracture each year, according to the National Osteoporosis Foundation, but less than a quarter are treated for osteoporosis afterwards.

A recent survey of 42 hip fracture patients found a startling level of misinformation and mismanagement surrounding osteoporosis. A majority (57%) said their doctors did not recommend osteoporosis medication and one in four said they would reject taking the drugs.

Nearly two-thirds (64%) of those who said they were being treated for osteoporosis were taking calcium and vitamin D supplements, which researchers say are "useless" at preventing osteoporotic fractures.

Another recent study found that elderly men are far less likely to be screened for osteoporosis or to take preventive measures against the bone-thinning disease than women. The risk of death after sustaining a hip fracture is twice as high in men compared to women.

Chronic Pain a ‘Silent Epidemic’ in UK

By Pat Anson, Editor

Nearly half of adults in the UK – nearly 28 million people – suffer from chronic pain, according to a new study in the British Medical Journal  that estimates about one in seven Britons have pain so severe it is disabling.

“Pain is really under-represented in terms of the public awareness of it,” lead author Alan Fayaz of Imperial College London said in The Guardian. “Nobody ever talks about chronic pain, it is like a silent epidemic.”

Fayaz and his colleagues conducted a meta-analysis of 19 studies involving nearly 140,000 people in the UK. Data from the studies was combined to arrive at the estimate that 43% of adults suffer from chronic pain – defined as pain that lasts for three months or more.

That estimate is over three times higher than a previous telephone survey study that found 7.8 million Britons have moderate to severe chronic pain.

About 8% of UK adults experience chronic neuropathic pain and 5.5% have fibromyalgia. Women are more likely to experience chronic pain than men.

Chronic pain was found to be a common experience among all age groups, including young adults, but increases steadily with age. Nearly two-thirds of adults over age 75 have chronic pain, according to one of the studies reviewed.

 “Bearing in mind that we are, in general an ageing population, that’s of concern because what you would then expect would be if you repeated this study in about 10 years time, the prevalence of chronic pain would be higher,” said Fayaz.

 “What I would really like is for us to have better tools in order for us to identify those people who are most severely affected and how we can help them, what their care needs are.”

The prevalence of chronic pain in the UK is similar to that in the United States, where the Institute of Medicine estimated that 40% of American adults – about 100 million people – have chronic pain.

New Molecules May Combat Immune System Disease

By Pat Anson, Editor

A team of international researchers may have unlocked an ancient secret in the human immune system that could lead to new treatments for rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease (IBD).

"Innate immunity is so old it goes all the way down to frogs, fish and even insects," says Professor Matt Cooper of the University of Queensland’s Institute of Molecular Bioscience.

Cooper and colleagues at Kings College London and the U. S. National Institutes of Health say the human immune system is basically comprised of two parts: the adaptive immune system, which produces antibodies against infection, and a very ancient pathway, known as the innate immune system.

"It stops us getting infections, but it also drives a lot of inflammatory diseases,” explains Cooper.  "So, in one case it's keeping us alive by stopping the bugs getting us, but if it goes wrong, we start to get diseases like arthritis, multiple sclerosis and IBDs such as colitis.

"Researchers always thought key components of these pathways acted alone, but our teams have discovered they can communicate and work together."

IBD is a chronic and painful inflammation of the gastrointestinal tract. Inflammation affects the entire digestive tract in Crohn’s disease, but only the large intestine in ulcerative colitis.

The study findings, published in the journal Science, may have significant implications for treating millions of people who suffer from inflammatory diseases.

"Inflammation in diseases such as colitis occurs when the immune system is activated inappropriately, and causes symptoms including pain, diarrhea, fever and weight loss," said Cooper. "Current treatments are not always effective, possibly because they are only blocking one of the key pathways and inflammation still occurs through the other pathway."

Researchers have developed two small molecules that each block one pathway.

activated immune cells

"We have tested these molecules and the results show that they both reduce inflammation when administered separately," Cooper said. "This work is still in the early stages but we are hopeful our ongoing research will lead to more effective treatments for the millions of IBD sufferers.

"It may give other scientists opportunities to develop new drugs against these diseases."

A healthy immune system is activated when the body recognizes invading microbes and alerts immune cells, such as T cells. Disease begins when the immune response spirals out of control and begins attacking healthy tissue.  

Researchers at New York University’s Langone Medical Center are also working on a theory known as the "hygiene hypothesis" that may explain why there is an increase in inflammatory bowel disease worldwide. They believe intestinal parasites and bacteria that humans were long exposed to are beneficial and help balance the immune system.

Sanitary practices have sharply reduced these parasitic and bacterial infections in developed nations, which now have some of the highest rates of Crohn’s and colitis. Researchers believe the immune response to infections triggers the growth of Clostridia, a bacterium known to counter inflammation.

Painkillers Cause Chronic Pain? Rats!!!

By Pat Anson, Editor

A provocative new study is likely to stir fresh debate about the risks associated with opioid pain medication. It’s not another study about addiction or overdose, but whether opioids actually increase chronic pain, a condition known as hyperalgesia. 

An international team of researchers found that even just a few days of morphine can make chronic pain last for several months by intensifying the release of pain signals in the spinal cord.

But there’s a catch. The research was conducted on laboratory rats.

"We are showing for the first time that even a brief exposure to opioids can have long-term negative effects on pain," said Peter Grace, PhD, an assistant research professor at the University of Colorado-Boulder's Department of Psychology and Neuroscience. "We found the treatment was contributing to the problem."

Grace and his colleagues found that damaged nerve cells in rats send a message to spinal cord immune cells known as glial cells, which normally act as "housekeepers" to clear out unwanted debris and microorganisms. The first signal of nerve pain sends glial cells into alert mode, priming them for further action.

"I look at it like turning up a dimmer switch on the spinal cord," said Grace.

Nerve pain was induced in the rats by slicing open their thighs. A fine thread was then tied around a major nerve. Over the next three months, researchers poked the rats' paws with stiff nylon hairs to see how sensitive they were to pain.

Injured rats that were not treated with morphine eventually recovered and did not show pain, but those that were treated with morphine for five days remained sensitive to pain. Researchers believe the morphine stimulated their glial cells and sent them into overdrive. They liken the effect to being slapped in the face twice.

"You might get away with the first slap, but not the second," said co-author Linda Watkins, a Distinguished Professor at CU Boulder. "This one-two hit causes the glial cells to explode into action, making pain neurons go wild."

"The implications for people taking opioids like morphine, oxycodone and methadone are great, since we show the short-term decision to take such opioids can have devastating consequences of making pain worse and longer lasting," said Watkins. "This is a very ugly side to opioids that had not been recognized before."

Patient advocates had a mixed reaction to the study.

“Linda Watkins is doing some awesome work. We know that glial cells are the key to pain generation. Exactly how is still poorly understood,” said Terri Lewis, PhD, a rehabilitation specialist who teaches in the field of Allied Health.  “We know that 'something' triggers inflammation and maintains it. When that trigger is turned up high, glial cells are activated."

“Generalizing from rats to humans is not okay. But if the same results are found in pigs, there is probably something to talk about,” added Lewis.

“There is enough evidence in humans that opioids work and do not make pain worse,” said Janice Reynolds, a retired nurse and patient advocate.  “Even the work in hyperalgesia has not, contrary to claims by opiophobics, translated well from rats to humans. The write up is extremely negative and tends to lead one to believe the results may be slanted or even poorly interpreted. The fact they are singling ‘chronic pain’ out is a warning sign.”

The CU-Boulder study, which is published online in the Proceedings of the National Academy of Sciences, does have an impressive pedigree, including researchers at the University of Adelaide in Australia, the University of North Carolina, the Chinese Academy of Sciences, the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and Tsinghua University in Beijing.

The study was funded in part by the American Pain Society, Australia's National Health and Medical Research Council, the National Natural Science Foundation in China, the National Institute on Drug Abuse, the National Institute of Dental and Craniofacial Research and the National Institute of Alcohol Abuse and Alcoholism.