Rats, Depression and Chronic Pain

By Pat Anson, Editor

An unusual study involving rats, depression and chronic pain is making headlines – the latest in a long line of flawed research studies being used to debunk the effectiveness of opioid pain medication.

“NIH study suggests opioid therapy not effective against chronic pain,” is the headline in UPI.

“Pain-induced changes in the brain explain the limited effectiveness of opioid therapy,” is how the Tech Explorist put it.

At issue is a small study by the National Institutes of Health (NIH) and McGill University in Montreal on pain-induced changes in 17 laboratory rats. That's right, 17 rats. The study findings, published in the journal Pain, concluded that chronic pain reduced the number of opioid receptors – the molecules that opioids bind to -- in the rats’ brains. In theory at least, that would make the rats less responsive to opioid pain medication.

Note that the research did not include any people, the rats were not given any opioids, and the effectiveness of opioids wasn't even measured in the rats. But that didn’t stop the NIH from drawing some sweeping conclusions.

“These results provide insights into why we see limited effectiveness of opioid therapy in chronic pain and the mechanism of the depression that may accompany it,” said David Shurtleff, PhD, acting director at the National Center for Complementary and Integrative Health (NCCIH).

“These basic research findings support NIH’s efforts to better understand chronic pain and comorbid symptoms and to develop better ways to help chronic pain patients effectively manage their pain.”

McGill University was more cautious, saying further studies were needed in humans to confirm the study findings.

“Although the study… was conducted in rats, and the results of animal studies may not be directly applicable to people, the findings provide new insights into how the brain may respond to pain and opioids,” a McGill press release states. “These findings, if confirmed in people, will enhance the understanding of the impact of chronic pain on the brain, its relation to depression, and the effects of opioids.”

Researchers have many theories about the origins and treatment of chronic pain, but conducting tests on humans to prove them is problematic. Laboratory animals are often used as an imperfect substitute.

In the NIH/McGill study, 17 rats had brain surgeries to produce a nerve injury that causes chronic pain, while another group of rats had sham surgeries (a similar procedure that did not cause chronic pain). Three months later, PET scan imaging showed opioid receptors had decreased in multiple regions of the brain in the nerve-injured rats, but no changes occurred in the sham-surgery rats.

These results suggest that pain itself, not treatment or pre-existing trauma, altered the brain’s opioid system. Other tests showed a weaker link between chronic pain and depression in the nerve-injured rats.

How did researchers determine the rats were depressed? 

When given a choice, healthy rats will normally drink water sweetened with sugar rather than plain water. But animals with a decreased ability to experience pleasure, a recognized symptom of depression, may not. The rats in the study with chronic pain showed a decreased preference for sugar water over plain water, while rats in the sham group still showed a preference for sweetened water. This, the researchers believe, was enough evidence to conclude the nerve-injured rates were depressed.

“It’s well known that there’s a link between chronic pain and depression,” explained co-author M. Catherine Bushnell, PhD, scientific director of NCCIH’s Division of Intramural Research.  “The results of this study indicate that pain-induced changes in the brain’s opioid system may play a role in this association. Animals with the greatest decrease in opioid receptor availability showed the greatest increase in depression-like symptoms after experiencing chronic pain.”

While intriguing, the results of this rat study are far from definitive and do not prove that opioids are an ineffective treatment for chronic pain in people. What they do show is that we need more and better research about opioids and chronic pain, not more misleading headlines and statements from the NIH.

The Search for a Chronic Pain Gene

By Roger Chriss, Columnist

The book “Chasing Men on Fire: The Story of the Search for a Pain Gene” by Yale University neuroscientist Stephen Waxman, MD, describes the hunt to understand and treat a rare neuropathic disorder called erythromelalgia – also known as burning man syndrome.

Inherited erythromelalgia is a rare painful neuropathy that causes severe burning pain and skin redness. Attacks are periodic and commonly triggered by heat, pressure, mild activity, exertion, insomnia or stress. The burning pain occurs in small fiber sensory nerves.

The book includes 13 research papers by Waxman and his team that illustrate the the process of discovering that the gene SCN9A is responsible for erythromelalgia, as well as idiopathic small fiber neuropathy. Waxman shows considerable understanding of the plight of people with these disorders.

“Since their neurological examinations were often normal, the complaints of patients with small fiber neuropathy -- which occurred without physical signs of disease of the nervous system that can be seen by the physician -- were, in the past, often dismissed as being of little consequence, or as having a psychological origin,” he wrote.

But the disorders are genetic. And understanding them has wide-ranging potential value. These mutations, once identified in families with rare inherited diseases, can teach us important lessons about other medical conditions.

Waxman cites the famous example of familial hypercholesterolemia, a rare metabolic dysfunction whose understanding led to the development of statin drugs.

Waxman’s work suggests that similar advances may be possible for other neuropathic pain disorders. Waxman and his research team found that “neuropathic pain reflects dysfunction of the nervous system and can occur when DRG [dorsal root ganglion] neurons take on a life of their own and generate pain signals even in the absence of a noxious stimulus or inflammation.”

Eventually, Waxman was able to show that one change in the genetic code for this gene was responsible. In other words, erythromelalgia and inherited small fiber neuropathy are the result of genetic mutations – debunking the theory that patients with these disorders have psychological issues.

“Surprisingly, despite their history of chronic pain, on psychological testing we found that only two subjects displayed signs of moderate anxiety and depression,” Waxman explains.

Rigorous clinical testing confirmed these ideas. Waxman and his team began by doing human studies on erythromelalgia, then moved on to small fiber neuropathy in 2010. They found evidence that genetic mutations may contribute to disorders of pain signaling. Understanding the exact pathophysiology of these painful neuropathies opens the door to new and more effective treatments.

“Identification of specific molecules that play key roles in axonal injury might provide a basis for therapies that would prevent, or slow, the degeneration of axons, thus halting or slowing the progression of peripheral neuropathy,” Waxman wrote.

The first drug tried was the sodium channel blocker carbamazepine. Pre-clinical studies in people confirmed that it does have a protective effect. Additional work using a research drug nicknamed “771” shows similar promise.

Research into leveraging this hard-won knowledge is ongoing. This work could ultimately lead to new treatments for a wide range of neuropathic disorders, including trigeminal neuralgia, diabetic neuropathy, and phantom limb pain.

The book “Chasing Men on Fire” amply illustrates the challenges of medical research and the importance of even seemingly small genetic variations in chronic neuropathic disorders. And it reminds us that rare disorders often provide invaluable insight into human disease and dysfunction that can benefit us all.

Roger Chriss lives with Ehlers Danlos syndrome and is a proud member of the Ehlers-Danlos Society. Roger is a technical consultant in Washington state, where he specializes in mathematics and research.

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.

Childhood Trauma Linked to Adult Pain

By Pat Anson, Editor

If you experienced physical or emotional trauma as a child – like a major illness, abuse or your parents’ divorce – you are more likely to experience pain as an adult, according to researchers at Penn State.

Their findings -- published in the Journal of Behavioral Medicine – add to previous research suggesting there’s a link between adult physical pain and childhood trauma or adversity.

"Pain is the number one reason people seek health care in the United States," said co-author Jennifer Graham-Engeland, PhD, a professor of biobehavioral health at Penn State. “We need more insight into pain and the phenomenon that can make pain both better or worse."

The researchers surveyed a diverse group of 265 adults who lived in a housing cooperative in the Bronx, New York.  All reported at least one form of trauma or adversity as children or adolescents. Some reported as many as seven.

A traumatizing event that left a person scared for years was the most common adversity (44%), followed by parental divorce (31%), a major illness or accident requiring hospitalization (24%), parental substance abuse (24%), sexual abuse (23%), parental unemployment (21%), a child’s removal from the home (10%) and physical abuse (10%).

Participants were also asked about their current mood, sleep patterns, optimism, how in control of their lives they felt, and if they recently felt pain.

Those who experienced more adversity or trauma as children were more likely to have mood or sleep problems as adults -- which in turn made them more likely to have physical pain. But the connection to pain was weaker in those who felt more optimistic and resilient.

"The participants who felt more optimistic or in control of their lives may have been better at waking up with pain but somehow managing not to let it ruin their day," said Ambika Mathur, a graduate student in biobehavioral health. "They may be feeling the same amount or intensity of pain, but they've taken control of and are optimistic about not letting the pain interfere with their day. They're still performing their work or daily activities while doing their best to ignore the pain."

The researchers found that childhood or adolescent adversity was strongly associated with more physical pain in adulthood, which could be partially explained by feelings of anger, depression or anxiety -- as well as poor sleep.

"Basically what's happening is mood and sleep disturbances are explaining the link between early life adversity and pain in adulthood," Mathur said. "The findings suggest that early life trauma is leading to adults having more problems with mood and sleep, which in turn lead to them feeling more pain and feeling like pain is interfering with their day."

The researchers also found that people who felt more optimistic or resilient didn't have as strong of a connection between trouble sleeping and pain interfering with their day. This suggests that childhood adversity can be overcome and doesn't necessarily sentence anyone to a lifetime of pain.

"This study does build on a body of research showing a connection between early life adversity and pain, but also that some people can achieve resilience," said Graham-Engeland. “Some people can be relatively resilient to adverse effects in the longer term, while others have a harder time."

Recent studies have also linked childhood trauma to adult migraine and fibromyalgia.

Major Depression Increasing

Pain sufferers aren't the only ones dealing with anxiety or depression. According to a new report from Blue Cross Blue Shield, major depression affects more than 9 million Americans who are commercially insured.

Diagnoses of major depression have risen by 33 percent since 2013. The rate is rising even faster in millennials (up 47%) and adolescents (47% for boys and 65% for girls).

In most cases, major depression coincides with a chronic or behavioral health condition. People diagnosed with depression are three times more likely to suffer from pain related disorders and injuries, and seven times more likely to have a substance use disorder.

It's worth noting that a recent study by the Substance Abuse and Mental Health Services Administration (SAMHSA) found that medications used to treat depression, anxiety and other mental health disorders are now involved in more overdoses than opioid pain medication.

Over 25,000 overdoses in 2016 were linked to "psychotherapeutic" medications such as antidepressants, benzodiazepines, anti-psychotics, barbiturates and attention deficit hyperactive disorder (ADHD) drugs such as Adderall. Deaths linked to psychotherapeutic drugs have risen by 45 percent since 2010.

Over 17,000 Americans died in 2016 from overdoses involving prescription opioids.

Breakthrough Blood Test Shows the ‘Color of Pain’

By Steve Weakley

A revolutionary new blood test developed by Australian researchers could give doctors instant insight into the severity of chronic pain by identifying colored biomarkers in the blood.  The “painHS” test uses advanced light spectrum analysis to identify the molecular structure of pain in immune cells.

“We are literally quantifying the color of pain,” explains neuroscientist Mark Hutchinson, PhD, a professor at the University of Adelaide Medical School in Australia.  “We’ve now discovered that we can use the natural color of biology to predict the severity of pain. What we’ve found is that persistent chronic pain has a different natural color in immune cells than in a situation where there isn’t persistent pain.”

Hutchinson and his colleagues discovered molecular changes in the immune cells of chronic pain patients. These pain biomarkers can be instantly identified through hyperspectral imaging, giving doctors the ability to measure a patient’s pain tolerance and sensitivity.

The test could potentially provide physicians with the first biology-based test to measure pain as the “5th vital sign” and to justify prescribing pain medication or other therapies.

Hutchinson was quick to point out that the test is not intended replace a patient’s description of pain to their physician.  Pain is subjective and varies from patient to patient, depending on their medical condition and many other factors.  Current tests used to measure pain in adults, such as the sad and smiley faces of the Wong-Baker pain scale, are so simple they were initially developed for young children.

“Self-reporting (by patients) is still going to be key but what this does mean is that those ‘forgotten people’ who are unable to communicate their pain conditions such as babies or people with dementia can now have their condition diagnosed and treated,” said Hutchinson, who believes the test could also revolutionize pain treatment in animals.

“Animals can’t tell us if they’re in pain but here we have a Dr. Doolittle type test that enables us to ‘talk’ to the animals so we can find out if they are experiencing pain and then we can help them."

Hutchinson says the test could also help speed the development of new drugs that could target particular kinds of chronic pain, and could eliminate the need for placebos in clinical trials by giving an instant indicator of a treatment’s effectiveness.

“We now know there is a peripheral cell signal, so we could start designing new types of drugs for new types of cellular therapies that target the peripheral immune system to tackle central nervous system pain,” he explained.

Hutchinson thinks the “painHS” test could be widely available to pain specialists and general practitioners in as little as 18 months and could provide a cost-effective tool to measure the severity of pain in patients with back problems, cancer, fibromyalgia, migraines and other conditions.

Several other blood tests have already been developed to diagnose patients with specific chronic pain conditions such as fibromyalgia.

IQuity Labs recently introduced a blood test that can identify fibromyalgia by analyzing ribonucleic acid (RNA) in blood molecules. EpicGenetics launched the first fibromyalgia blood test in 2013. That test looks for chemokines and cytokines, which are protein molecules produced by white blood cells.

Light Therapy Used to Treat Neuropathic Pain

By Pat Anson, Editor

For someone with peripheral neuropathy, even the slightest touch can cause burning, stinging or shooting pain, usually in the hands or feet.

The pain is caused when the peripheral nervous system is damaged by diabetes, shingles, chemotherapy or some other medical condition. About 8% of adults worldwide suffer from some form of neuropathy. Medications prescribed to dull the pain – such as opioids, anti-depressants or gabapentin (Neurontin) -- often prove to be ineffective, don’t last long or have unwanted side effects.

Scientists in Italy have now discovered an experimental way to treat neuropathy that provides pain relief for weeks at a time without the use of medication. In experiments on laboratory mice, researchers at the European Molecular Biology Laboratory (EMBL) in Rome identified a specific set of nerve cells in mouse skin that play a significant role in neuropathic pain.

NATURE COMMUNICATIONs

When injected with a light-sensitive chemical and then exposed to infrared light, the nerve cells pull away from the skin’s surface and stop sending pain signals. The pain-relieving effects of the light therapy appear to last for weeks.

The accompanying image shows the skin of a mouse, with the nerve cells that are responsible for sensitivity to touch highlighted in green. The neurons are primarily located around hair follicles.

The EMBL's research, first reported in the journal Nature Communications, is still in its early stages. But scientists say human skin tissue is similar to that of mice, indicating that light therapy might be effective in managing neuropathic pain in humans.

"In the end, our aim is to solve the problem of pain in both humans and animals," says Paul Heppenstall, PhD, EMBL group leader. "Of course, a lot of work needs to be done before we can do a similar study in people with neuropathic pain. That's why we're now actively looking for partners and are open for new collaborations to develop this method further, with the hope of one day using it in the clinic."

Heppenstall says light therapy works on the treated nerve cells the same way spicy food or capsaicin patches can cause nerve fibers to retract.  

"It's like eating a strong curry, which burns the nerve endings in your mouth and desensitizes them for some time," says Heppenstall. "The nice thing about our technique is that we can specifically target the small subgroup of neurons causing neuropathic pain."

There are many different types of nerve cells in skin, which respond to different sensations like vibration, cold, heat or normal pain. Researchers say those cells are not affected by the light treatment. The skin is only desensitized to a gentle touch, breeze, or tickling.

Previous attempts to develop drugs to treat neuropathic pain have mostly focused on targeting single molecules.

"We think however, that there's not one single molecule responsible, there are many," Heppenstall explains. "You might be able to succeed in blocking one or a couple, but others would take over the same function eventually. With our new illumination method, we avoid this problem altogether."

The neuropathic pain in mice was assessed with a simple touch. The mice would normally quickly withdraw their paw when it was gently touched, but after light therapy they exhibited normal reflexive response to touch. The effect of the therapy lasted for a few weeks, until the nerve endings grew back and the gentle touch caused pain again.

Human Rights Watch Investigating U.S. Pain Treatment

By Pat Anson, Editor

Human Rights Watch is well-known internationally for its groundbreaking reports on human rights violations around the world. The organization has recently reported on the torture of prisoners in Sri Lanka, forced labor in Thailand, and corruption and mass arrests in Saudi Arabia.

Pain News Network has learned the New York-based non-profit is turning its attention closer to home – by launching an investigation into the treatment of chronic pain patients in the United States. The impetus for the investigation began when researchers were studying the treatment of cancer and palliative care patients – and began to see poorly treated pain as a human rights issue.

“People we interviewed who didn’t have access to appropriate medications for their pain were essentially giving testimony that was almost exactly the same as the testimony we were getting from the victims of police torture,” says Diederik Lohman, Director of Health and Human Rights for Human Rights Watch.

“And we realized this was actually one of those issues that almost no one was paying attention to. People were facing tremendous suffering that actually could be relieved pretty easily through very inexpensive palliative care and pain management.”

In many third world countries, Lohman says opioid pain medications like morphine are difficult to obtain, even for patients dying of cancer.

“They would say the pain was just unbearable, that they would do anything to make it stop, and many of them would tell us that they asked their doctors to give them something to put them out of their misery,” he told PNN.

Recently those same stories have been coming from pain patients in the United States.  

“As we started looking at this issue more closely, we started hearing more and more stories of chronic pain patients in the U.S. who had been on opioids, who were being told by their physicians that 'We have to take you off.'  And we started hearing stories of patients who were having a lot of trouble finding a doctor who’s willing to accept them as a patient,” said Lohman.

Lohman says Human Rights Watch is well aware of the addiction and overdose crisis in the U.S. But he says the “right balance” needs to be found between keeping opioids off the street and making sure medications are still available to legitimate patients.

‘CDC Clearly Knows What’s Going On’

Part of the investigation will focus on the role played by the opioid guidelines released by the Centers for Disease Control and Prevention in 2016, which discourage doctors from prescribing opioids for chronic pain. Although voluntary and intended only for family practice physicians, the CDC guidelines have been widely adopted as mandatory rules by other federal agencies, states and insurers.  

The impact of the guidelines was sudden and powerful. Within a year of their release, a PNN survey of over 3,100 pain patients found that 71 percent had their opioid medication stopped or reduced. Nearly 85% said their pain and quality of life were worse.

“The CDC clearly knows what's going on and they haven’t taken any real action to say, ‘That is not appropriate, involuntarily forcing people off their medications. That’s not what we recommended,'" Lohman said. “When a government puts in place regulations that make it almost impossible for a physician to prescribe an essential medication, or for a pharmacist to stock the medication, or for a patient to fill their prescriptions, that becomes a human rights issue.”

Human Rights Watch is looking for testimonials from chronic pain patients who have been forced or encouraged to stop their opioid medication by physicians or pharmacists. They’d also like to hear from patients who have been forced or encouraged to seek alternative forms of treatment, but who then found those treatments financially or geographically inaccessible.

Input from doctors affected by the opioid guidelines, regulations and anti-opioid climate is also welcome.

Investigators are particularly interested in hearing from patients and doctors in West Virginia, Massachusetts, Maine, Washington, North Carolina, Florida and Montana.

“Our work is heavily reliant on the testimonies of people who are directly affected. That’s been our methodology of work for many years,” says Lohman. “We would like for our work to actually help move things in the right direction. But it’s important to document what’s going on.”

(Update: Human Rights Watch has been flooded with responses to this story. At this time, they do not need any additional stories from pain patients. They plan to complete their investigation and release their findings by the end of the year.)

Osteoarthritis Drug Works No Better Than Placebo

By Pat Anson, Editor

Hydroxychloroquine (Plaquenil) is a medication commonly used to treat rheumatoid arthritis, lupus and other autoimmune diseases. It’s also being prescribed off-label to treat inflammation and pain caused by hand osteoarthritis, a joint condition that affects nearly a third of patients over the age of 70.

But in a new study published in the Annals of Internal Medicine, British researchers reported that hydroxychloroquine is no more effective than a placebo in relieving moderate to severe pain caused by hand osteoarthritis.

Researchers at the Leeds Institute of Rheumatic and Musculoskeletal Medicine and the Leeds Biomedical Research Centre randomly assigned 248 patients with radiographic hand osteoarthritis to either hydroxychloroquine (200 to 400 mg) or placebo for a year.

Most of the patients had symptoms of hand osteoarthritis for about 5 years, and their average pain level was 7 out of 10.

After 3, 6 and 12 months, there were no significant differences in treatment outcomes between the hydroxychloroquine and placebo groups.

“We found that HCQ (hydroxychloroquine) was not a more effective analgesic than placebo when added to usual care in persons with moderate to severe hand osteoarthritis,” researchers reported. “Background analgesic use did not differ between groups, and baseline inflammation and structural damage did not affect response to HCQ. The study therefore presents no evidence that HCQ should be considered within the management plan of patients with hand osteoarthritis.”

Two doctors who reviewed the study say more research is needed to find drugs that can treat the inflammation caused by hand osteoarthritis, a condition for which there are no effective therapies.

“The negative findings in this carefully done trial beg the question of what went awry. Did HCQ fail to reduce inflammation, or did reduced inflammation not translate to pain relief?” wrote Elena Losina, PhD, and Jefferey Katz, MD in an editorial.

“Although HCQ is safe, it is also a weak anti-inflammatory agent seldom used in contemporary practice as a solo disease-modifying therapy for rheumatoid arthritis and other inflammatory conditions. Further therapeutic studies of the effects of anti-inflammatory therapy on nodal hand osteoarthritis will need to use more potent agents or compounds developed to more specifically target the inflammatory pathways documented in this condition.”

Does MSG Cause Chronic Pain?

By Pat Anson, Editor

Monosodium glutamate (MSG) is a naturally occurring amino acid that is widely used in processed food and soups as a flavor enhancer. There have been many anecdotal reports of MSG causing headaches, nausea and fatigue – but the Food and Drug Administration found no evidence of that and declared that MSG is “generally recognized as safe.”

A small pilot study in central Africa suggests otherwise.

Researchers at the University of Michigan and American University in Washington DC wanted to know why so many people in Meru, Kenya have widespread chronic pain – nearly two-thirds according to one survey. Most suffered from neurological problems, including headaches or migraines, chronic fatigue, cognitive dysfunction, and sleep issues.

Researchers recruited 30 Meru residents for a study to see if diet and dehydration played a role in their symptoms, focusing on a local seasoning spice called mchuzi mix, which often contains MSG. The spice mix is known as the “flavor of Kenya” and is commonly used in multiple dishes throughout the day.

When some of the study participants were sent home with a mchuzi mix containing no MSG and urged to drink more water, they started showing significant improvement in their pain symptoms within two weeks. Many liked the flavor of the new mix and asked for more.

"This preliminary research in Kenya is consistent with what I am observing in my chronic pain research here in the United States," said Kathleen Holton, PhD, a nutritional neuroscientist at American University and lead author of the study published in the journal Nutrition.

"We don't know what exposure is leading to this susceptibility to dietary glutamate, but this pilot study suggests the need for a large-scale clinical trial, since dietary change could be an effective low-cost treatment option for developing countries."

Holton and her colleagues believe glutamate may act as a neurotransmitter in the brain and stimulate nerve cells. Increased consumption of glutamate may also enhance the central sensitization that leads to chronic pain.

“These preliminary findings support the hypothesis that MSG may be able to modulate pain response, and suggest that a future larger study is feasible and warranted in this population,” said Holton.

Researchers are planning a larger epidemiological survey to understand the prevalence of widespread chronic pain in the region and to train Kenyans on how to conduct a large-scale clinical trial. The goal is to see if dietary change could be an effective, low-cost treatment option for chronic pain.

"This would be incredible if we could impact chronic pain simply by making slight modifications to diet," said Daniel Clauw, MD, a University of Michigan professor and a leading expert on chronic pain.

Vitamin D Supplements Could Ease Symptoms of IBS

By Pat Anson, Editor

A new study suggests that Vitamin D supplements may help ease stomach cramps, constipation and other painful symptoms of irritable bowel syndrome (IBS).

In a systematic review (a study of studies) involving hundreds of patients around the world, British researchers found that over half the patients with IBS had low levels of Vitamin D in their blood serum. Vitamin D supplements helped improve symptoms for some patients, although the findings were mixed.

"The available evidence suggests that low vitamin D status is common among the IBS population and merits assessment and rectification for general health reasons alone,” said Claire Williams of the University of Sheffield, lead author of the study published in the European Journal of Clinical Nutrition.

"An inverse correlation between serum vitamin D and IBS symptom severity is suggested and vitamin D interventions may benefit symptoms."

Williams and her colleagues cautioned that the evidence was not strong that supplements would help, and said larger studies were needed to build a case for Vitamin D as a treatment for IBS.

Britain’s National Health Service was also cautious about the findings.

“Although this possible link is worth investigating further, the evidence is currently very limited. The results seen in this study are an extremely mixed bag taken from studies of questionable quality," the NHS said in a review.

“The observational studies mainly just show that a number of these people with IBS also had a vitamin D deficiency. But you could select many other samples of people with IBS and find they have sufficient vitamin D levels, or other people who don't have IBS but who are vitamin D deficient.”

Both IBS and vitamin D deficiency are common in the western world. About 20% of adults in the UK are deficient in Vitamin D. Low levels of the “sunshine vitamin” have also been linked to fibromyalgia and multiple sclerosis. 

Most people get all the Vitamin D they need by being exposed to ultraviolet rays in sunlight. You can also get it by eating foods rich in Vitamin D, such as oily fish and eggs. Vitamin D has a wide range of positive health effects, such as strengthening bones and inhibiting the growth of some cancers.

Why Does Menopause Worsen Rheumatoid Arthritis?

By Pat Anson, Editor

A large new study is confirming what many women with rheumatoid arthritis (RA) already know – menopause and hormonal changes can significantly worsen their pain and other symptoms. But it's not clear why that happens.

Researchers at the University of Nebraska Medical Center enrolled over 8,000 women with RA – both young and old -- in their observational study. They found that post-menopausal women with RA had a significant increase in the level and rate of functional physical decline. Menopause was also associated with a worsening progression of the disease.

RA is a chronic and disabling autoimmune disease in which the body’s own defenses attack joint tissues, causing pain, inflammation and joint erosion. Women experience RA at a rate three times greater than men, have more severe symptoms and increased disability.

Previous studies have shown that women with RA experience changes in their disease during reproductive and hormonal changes. During pregnancy, women are less likely to develop RA, yet the disease is more likely to progress and flare during the post-partum period. Similarly, women who experience early menopause are more likely to develop RA compared to those who experience normal or late menopause.

Hormone levels of estrogen increase during pregnancy and decline during menopause – but the association with RA is not fully understood.

"Further study is needed as to why women with rheumatoid arthritis are suffering a greater decline in function after menopause," said the study's lead author, Elizabeth Mollard, PhD, an assistant professor in the College of Nursing at the University of Nebraska Medical Center.

"Not only is this decline causing suffering for women, it is costly to both individuals and the healthcare system as a whole. Research is specifically needed on the mechanism connecting these variables with the eventual goal of identifying interventions that can maintain or improve function in postmenopausal women with rheumatoid arthritis."

The study is published in the journal Rheumatology.

RA affects about 1.3 million Americans and about one percent of the global population. Until the late 1990s, one in three RA patients were permanently disabled within five years of disease onset.

Although there are still no cures for RA, in recent years there has been significant improvement in treatment, with disease control now possible for many patients who receive biologic drugs. Those treatments are expensive, with some biologic therapies costing $25,000 a year.

Losing Weight Helps Lower Pain Levels

By Pat Anson, Editor

Those of us who made a New Year’s resolution to lose weight have a little more incentive to keep our pledge – thanks to new research showing that even a small weight loss reduces overall body pain, as well as fatigue and depression.

The University of Michigan study, published in The Journal of Pain, involved 123 obese participants who were put on a low-calorie liquid diet for 12 weeks and asked to gradually increase their physical activity. The goal was to lose at least 10 percent of their body weight.

“It’s been known for some time that people who are obese tend to have higher levels of pain, generally speaking,” says Andrew Schrepf, PhD, a research investigator at Michigan Medicine’s Chronic Pain and Fatigue Research Center. “But the assumption has always been the pain is going to be in the knees, hips and lower back — parts of the body that are weight-bearing.”

Schrepf and his colleagues found that losing weight not only lowered pain levels in the knees and hips, but in unexpected areas such as the abdomen, arm, chest and jaw. Study participants who could reach the goal of losing 10% of their weight also reported better mental health, improved cognition and more energy. Men in particular showed improvements in their energy levels.

The results are significant because previous research hasn’t shown how weight loss affects widespread pain throughout the body.

“We know when people lose a lot of weight they tend to feel better,” Schrepf says. “But astonishingly, no one ever looked at where in the body the pain gets better.”

Researchers surveyed participants about their pain and other symptoms before and after the 12 week diet, using fibromyalgia assessment criteria to make their determinations. Participants were also evaluated and counseled by physicians and dietitians who specialize in endocrinology and obesity medicine.

Of the 123 participants, 99 were able to lose 10 percent or more of their body weight.

“The focus in the program is on calorie restriction and long-term weight loss, although all patients are encouraged to get more physically active for the other health benefits that exercise provides,” says Amy Rothberg, MD, an associate professor of endocrinology nutritional sciences at U-M. “The truth is people are, paradoxically, far more energetic on a low-energy diet and find after they begin losing weight that they can do more and are more physically active.”

Participants who met the weight loss goal reported widespread improvement in pain compared to those who did not. Their blood samples also showed a spike in anti-inflammatory molecules — a key weapon in fighting many types of pain. Researchers say the widespread improvement in body pain suggests that joints aren’t the only conduit of chronic pain.

“What we think that means is this process of losing weight may be affecting the central mechanisms of pain control related to the brain and spinal cord,” said Schrepf.

In future research, the team hopes to better understand why losing 10% of body weight was the dividing line for reduced pain.

“Some of your earliest weight loss isn’t all fat; it could be water,” Schrepf says. “Somewhere around 10 percent we’re reaching some kind of critical mass, but it’s hard to know exactly what that means.”

The Difference Between Intractable and Chronic Pain

By Forest Tennant, MD, DrPH

The current attempts by a number of parties to castigate and humiliate pain patients and their medical practitioners is not just pathetic and mostly false, it is dangerous to the fate and life of many intractable pain (IP) patients.  If it wasn’t so serious, some of the claims, biases and beliefs would make good comedy.

First and foremost there has been no discussion about the difference between intractable pain and chronic pain.  There really is no bigger issue. 

The proper identification and treatment of the IP patient is not only essential for the health and well-being of the IP patient, it is a major key to the prevention of overdoses and diversion of abusable drugs.  IP patients must have special care and monitoring.  

The basic definition of IP is a “moderate to severe, constant pain that has no known cure and requires daily medical treatment.” 

Chronic pain, on the other hand is a “mild to moderate, intermittent, recurring pain that does not require daily medical treatment.” While there are millions of persons with chronic pain, only about 10% are intractable.

The cause of “intractability” is two-fold:

1. The initial injury or disease which initiated IP was severe enough to cause a pathologic transformation of the microglial cells in the spinal cord and/or brain. It is this transformation that produces neuroinflammation and the constancy of the pain. This process is known as “centralization” or “central sensitivity.”

2. To have enough injury to cause “centralization” one must have a most serious disease or condition of which the most common are: adhesive arachnoiditis, traumatic brain injury, reflex sympathetic dystrophy, post-viral encephalopathy, or a genetic disease such as Ehlers-Danlos Syndrome, porphyria, or sickle cell disease.

Medical practitioners must have minimally-restricted prescribing authority and autonomy to adequately treat IP.  For example, the proper treatment of IP not only requires analgesics, opioids and non-opioid, but specific anti-inflammatory, hormonal, and corticosteroid agents that will cross the blood brain barrier and control inflamed and pathologic microglial cells.  Treatment of IP has to be individually tailored and may require non-standard, off-label, or an unusual treatment regimen.  

Make no mistake about it.  The new treatment approach to IP is quite effective in reducing pain, controlling neuroinflammation, and allowing patients to biologically function well enough to have a good quality of life.  Also be advised that the new IP approach is not just reducing pain but treating the underlying cause of pain.  Consequently, a lot of expensive procedures, therapies, and opioids are no longer needed. 

As long as I am practicing I will continue to push forward this new approach.

Dr. Tennant specializes in the research and treatment of intractable pain at the Veract Intractable Pain Clinic in West Covina, California, which remains in operation after recently being raided by DEA agents. Many of Dr. Tennant's patients travel from out-of-state because they are unable to find effective treatment elsewhere.

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.

Fibromyalgia Linked to Overactive Brain Networks

By Pat Anson, Editor

Many fibromyalgia sufferers have been told that the pain is “all in their head.” New research indicates there may be some truth to that, and that overactive brain networks could play a role in the hypersensitivity of fibromyalgia patients.

Fibromyalgia is a poorly understood disorder characterized by deep tissue pain, fatigue, headaches, mood swings and insomnia. There is no known cause and successful treatments have been elusive.

In a lengthy study published in the journal Scientific Reports, an international team of researchers at the University of Michigan and in South Korea report that patients with fibromyalgia have brain networks primed for rapid responses to minor changes. This abnormal hypersensitivity is known as called explosive synchronization (ES).

"For the first time, this research shows that the hypersensitivity experienced by chronic pain patients may result from hypersensitive brain networks," says co-senior author Richard Harris, PhD, an associate professor of anesthesiology at Michigan Medicine’s Chronic Pain and Fatigue Research Center.

In ES, a small stimulus can lead to a dramatic synchronized reaction throughout the network, as can happen when a power outage triggers a major grid failure or blackout. Until recently, this phenomenon was studied in physics rather than medicine. Researchers say it's a promising avenue to explore in the quest to determine how a person develops fibromyalgia.

"As opposed to the normal process of gradually linking up different centers in the brain after a stimulus, chronic pain patients have conditions that predispose them to linking up in an abrupt, explosive manner," says first author UnCheol Lee, PhD., a physicist and assistant professor of anesthesiology at Michigan Medicine.

The researchers tested their theory by conducting electroencephalogram (EEG) tests on the brains of 10 female patients with fibromyalgia. Baseline EEG results showed the patients had hypersensitive brain networks, and that there was a strong correlation between the degree of ES conditions and the self-reported intensity of their pain during EEG testing.

Lee's research team and collaborators in South Korea then used computer models of brain activity to compare the stimulus responses of the fibromyalgia patients to those of healthy ones. As expected, the fibromyalgia model was more sensitive to electrical stimulation.

"We again see the chronic pain brain is electrically unstable and sensitive," Harris says.

Harris says this type of modeling could help guide future treatments for fibromyalgia. Since ES can be modeled outside of the brain in computers, researchers can test for influential regions that transform a hypersensitive network into a more stable one. These regions could then be targeted in living humans using noninvasive brain modulation therapies such as transcranial magnetic stimulation, which is currently used to treat fibromyalgia and depression.

“We expect that our study may ultimately suggest new approaches for analgesic treatments. ES provides a theoretical framework and quantitative approach to test interventions that shift a hypersensitive brain network to a more normal brain network,” researchers reported. 

“It may be possible to convert an ES network to a non-ES network just by modulating one or two hub nodes. Indeed, transcranial magnetic stimulation and/or transcranial direct current stimulation may be improved by ‘targeting’ these sensitive hub nodes. The application of deep brain stimulation to critical nodes that could modify ES conditions is another therapeutic possibility that could be explored.”

The research was funded by the Cerephex Corporation, James S. McDonnell Foundation, and the National Institutes of Health

Scientists Building a Safer Opioid

By Pat Anson, Editor

Researchers at the University of North Carolina believe they’ve found a way to create a new type of opioid medication that relieves pain without risky side effects.

Currently, opioid painkillers bind to several opioid receptors on the surface of brain cells, triggering a wide range of side effects -- from nausea, numbness and constipation to anxiety, addiction and potentially fatal respiratory depression.

The UNC researchers report in the journal Cell that they have created a new drug compound that only activates the kappa opioid receptor – the brain receptor that is the key to pain relief.

"To create better opioids, we need to know the structure of their receptors," said senior author Bryan Roth, MD, a professor in the Department of Pharmacology at UNC School of Medicine.

"Until recently, this was impossible. But now we know the structure of the activated kappa opioid receptor. And we showed we can actually use the structure to make a drug-like compound with better properties than current opioids."

The compound was created in cell cultures in Roth's lab, and still needs to be tested in animal models. But knowing the detailed structure of the kappa opioid receptor (KOR) has opened the door to developing other drug-like compounds that are highly selective for specific opioid receptors.

KAPPA OPIOID RECEPTOR (unc IMAGE)

"Tens of thousands people who take opioids die every year, and so we need safer and more effective drugs for treating pain and related conditions," Roth said in a news release. "One of the big ideas is to target KORs because the few drugs that bind to it don't lead to addiction or cause death due to overdose. Those side effects are mainly related to actions at the mu opioid receptor."

Drugs that bind to KORs can still have side effects, such as hallucinations and dysphoria - a state of unease or dissatisfaction with life related to anxiety and depression. That is why scientists say it’s important to know how this receptor is activated – so they can figure out a way to bind a compound to KORs so that it only relieves pain.

"Now we have a much better understanding of the direction we have to explore in order to create a selective drug to activate only kappa opioid receptors," said corresponding author Daniel Wacker, PhD, UNC School of Medicine.

The UNC research was funded by the National Institutes of Health, the Mayday Fund, and the Peter F. McManus Trust.

Genetics Play Significant Role in Post-Surgical Pain

By Pat Anson, Editor

An important new study has confirmed that a patient’s genes really do play a role in determining whether they develop chronic pain after surgery.

Researchers in China collected blood samples from 1,152 surgical patients to look for genetic variations in 54 "pain-related" genes which have been associated with pain sensation. Patients were then contacted a year later to see if they had chronic post-surgical pain.

A surprising number – one out of five patients – still experienced pain at the wound site, and 33 percent of them said their pain was severe.  Patients with pain also reported problems with their overall health, as well as daily activities such as mood, walking, relations with others, sleep, and quality of life.

Aside from genetic factors, the study also found patients younger than 65, males, and those with a prior history of chronic pain were at increased risk. The study is published online in the journal Anesthesiology.

"Our study not only shows there are common genetic variations among people that may help to identify whether they are at high-risk for developing chronic pain after surgery, but it also helps explain why only a fraction of patients ever even experience persistent pain," said lead researcher Matthew T.V. Chan, MD, at the Chinese University of Hong Kong.

"Until now, the genetic variations associated with chronic post-surgical pain have not been well identified."

One genetic variation in particular - a gene found in the nervous-system called brain-derived neurotrophic factor (BDNF) - was found to be most frequently associated with chronic post-surgical pain. Researchers confirmed the finding in a study on laboratory mice.

The researchers also found that genetic variations account for a higher percentage of chronic post-surgical pain (between 7 percent and 12 percent) than other risk factors such as age, sex, smoking history or anesthesia technique (between 3 percent and 6 percent).

Chronic post-surgical pain is one of the most common and serious complications after surgery. Previous studies have found that chronic pain was common after abdominal hysterectomies (25.1%) and heart or lung surgery (37.6%).

“Considering that more than 230 million surgeries are performed each year worldwide, the data would imply that millions of patients will continue to suffer wound pain, months to years after their surgery,” researchers said.

The study comes at a time when many U.S. states have adopted or are enacting laws that would limit the supply of opioid medication to just a few days for acute short-term pain. Minnesota, for example, is close to adopting strict guidelines that would limit the dose and supply of opioids to three days for acute pain and seven days after a major surgery.