Genetic Variations Involved in a Third of CRPS Cases

By Pat Anson, PNN Editor

Chronic Regional Pain Syndrome (CRPS) is one of the worst and most baffling of pain conditions. It usually starts after an injury to an arm or leg, with the skin in the affected area becoming warm, red and painful to touch. Most cases are mild and people recover after a few months, but in rare cases the condition grows worse, resulting in intense nerve pain that can spread and last for years.

Why do some people develop CRPS, while others get better? A small new study in the UK suggests that a genetic variant may be responsible for about a third of CRPS cases.

Researchers at the University of Cambridge took blood samples from 84 patients enrolled in the CRPS-UK Registry to look for variations in certain genes known as single nucleotide polymorphisms, or SNPs for short. Their DNA was compared to a control group of patients with chronic pain from fibromyalgia and low back pain.

Their findings, recently published in the Journal of Medical Genetics, show that an SNP in 4 genes (ANO10, P2RX7, PRKAG1 and SLC12A9) was “more common than expected” in patients with CRPS for at least a year (CRPS-1) than it was in the fibromyalgia/back pain group.

In all, 25 of the 84 patients (30%) with CRPS-1 had the variations in at least 1 of the 4 genes. None of the variations was found in the control group.

Interestingly, men with CRPS were more likely to have the variations (57%) than women (24%), although the sample sizes are so small the discrepancy will need to be confirmed in a larger study. In real life, women are more likely to have CRPS than men.

“This raises the possibility of different mechanisms of disease in males and females in CRPS-1 and that therapeutic responses may also be influenced by sex,” wrote lead author C. Geoffrey Woods, a clinical geneticist at the Cambridge Institute for Medical Research.  “Our data support an underlying genetic predisposition to CRPS-1 in up to a third of cases, with this effect being most prominent in males.”

There may be a biological explanation for the findings, because the ANO10, P2RX7and SLC12A9 genes are found in immune cells of the peripheral nervous system, which becomes inflamed by CRPS.

All 4 genes are also expressed in macrophages — a type of white blood cell involved in the immune response of healthy people. This suggests that variations in those 4 genes may be what triggers CRPS, which is also known as Reflex Sympathetic Dystrophy (RSD).

CRPS/RSD is difficult to treat and there is no known cure. Some patients have found relief through Scrambler therapy and ketamine infusions.

Long Covid May Affect Genes Involved in Pain Signaling

By Pat Anson, PNN Editor

About 16 million people in the United States have Long Covid, a poorly understood disorder that causes body aches, headaches, fatigue, insomnia, brain fog and other symptoms long after an initial infection with COVID-19. For some, the symptoms are mild, but for other they are so severe they become disabling.

Why do some people quickly recover from Covid, while about one in five have lingering symptoms?

A new animal study found that thousands of genes involved in nervous system function are affected by SARS-CoV-2, and may cause lasting damage to dorsal root ganglia, the spinal nerves that carry pain and other sensory messages to the brain. Scientists believe that genetic damage may be what causes Long Covid.

“Several studies have found that a high proportion of Long Covid patients suffer from abnormal perception of touch, pressure, temperature, pain or tingling throughout the body. Our work suggests that SARS-CoV-2 might induce lasting pain in a rather unique way, emphasizing the need for therapeutics that target molecular pathways specific to this virus,” explains co-author Venetia Zachariou, PhD, chair of pharmacology, physiology & biophysics at Boston University’s Chobanian & Avedisian School of Medicine.

Zachariou and her colleagues infected hamsters with SARS-CoV-2 and studied how it affected the animals’ sensitivity to touch, both during the initial infection and after the infection had cleared. Then they compared the effects of SARS-CoV-2 to those triggered by an influenza A virus infection, and were surprised by what they found.

In the hamsters infected with Covid, researchers observed a slow but progressive increase in sensory sensitivity over time – one that differed substantially from influenza A infections, which caused a sudden hypersensitivity that returned to normal once the initial infection ended.

Although the studies were performed on animals, researchers say they align with the acute and chronic symptoms caused by Covid in humans. They hope further studies on human genes and sensory pathways affected by the Covid virus will lead to new treatments for Long Covid and conditions such as ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome),

“We hope this study will provide new avenues for addressing somatosensory symptoms of long COVID and ME/CFS, which are only just now beginning to be addressed by mainstream medicine. While we have begun using this information by validating one promising target in this study, we believe our now publicly available data can yield insights into many new therapeutic strategies,” adds Zachariou. 

The study findings appear online in the journal Science Signaling.

The federal government’s Covid public health emergency officially ends this week, but the impact of the pandemic will likely be felt for years to come.

Genetic Studies Could Pave the Way to New Pain Treatments

By Dr. Lynn Webster, PNN Columnist

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

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

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

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

The Individuality of Pain

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

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

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

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

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

The Heredity Nature of Pain

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

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

The Genetics of Analgesia

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

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

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

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

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

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

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

Neanderthal Gene Makes Us More Sensitive to Pain

By Pat Anson, PNN Editor

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

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

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

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

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

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

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

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

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

Consumer DNA Tests Do Not Accurately Predict Disease

By Dr. Lynn Webster, PNN Columnist

Three years ago, I gave my family members DNA kits as Christmas gifts. I thought the genetic health aspects of the test would be an entertaining exercise -- a bit like visiting a psychic who would read tarot cards to predict the future. I didn’t think of it as a serious medical test, and I made sure my family understood that.

These kits have become very popular. More than 26 million people have taken an at-home genetics test, hoping to learn more about their ancestral background, along with their risks of developing certain diseases. But the tests may not live up to either of those expectations.

The U.S. Government Accountability Office (GAO) sent a report to Congress in 2010 alleging that some DNA testing companies used deceptive marketing and other questionable practices. 

The GAO stated that results from DNA tests were “misleading and of little or no practical use.” Their investigation also uncovered the fact that different DNA testing companies provided different results from the same sample. 

Not only were the test results dubious, but the companies made some deceptive claims. One company alleged the results from their testing could help cure diseases. Another claimed the data could predict at which sports a child would excel.

Admittedly, the accuracy of the tests has improved since 2010, but the tests still are, at best, imperfect.

Our genome (the whole of our hereditary information, encoded in our DNA) contains about three billion genes. Of those, only about 20,000 are responsible for disease. But we are more than our genes. Whether or not we will get most diseases depends on a combination of our genes and environment. This interaction of environment and genes is what we call a phenotype.

Of course, there are genetic mutations that are responsible for specific diseases. Single-gene mutations are responsible for about 10,000 diseases, the majority of which are considered rare. Some of the more common single-gene disorders include sickle cell anemia, cystic fibrosis, phenylketonuria, and Huntington's disease.

However, there is no guarantee that direct-to-consumer DNA kits are capable of detecting all common single genetic mutations. Moreover, the absence of a reported mutation from these kits does not mean the mutation does not exist.

Testing may uncover some benign and interesting traits, though. For example, some genetic kits (but not all) can tell you if you have a gene associated with how your earlobes are shaped, whether your urine has an offensive odor after you eat asparagus, or if you are inclined to dislike cilantro.

The accuracy of the health-related portion of the tests is improving. It is now possible to test for genes that predict a person's risk for certain types of breast and prostate cancers. However, placing too much weight on the results of those tests can be dangerous. For example, the tests do not screen for all types of breast cancer, which can lead consumers to falsely conclude their risk of all breast cancers is low if their test results do not indicate a gene mutation associated with breast cancer.

At best, the types of DNA tests that provide information on single-mutation diseases should be accompanied by appropriate genetic counseling. Since most diseases are based on multiple genes and environment, a genetics counselor can help put the test results into perspective.

Deciding how to use the information may be more important than knowing the results of the test. In medicine, we never order a test unless it will help us provide better care for our patient. This may be an important principle to apply here as well.

Privacy Is a Big Concern

We should also be very concerned about how our DNA data will be stored and used. The testing companies' DNA databases can be hacked by people with nefarious motives, or shared with insurance companies or law enforcement. Laws protecting consumers are evolving, but clearly, at-home DNA tests expose consumers to unknown and, perhaps, unintended consequences.

DNA tests were first pitched to consumers as a way in which they could learn about their ancestry. However, the reference data sets were largely European and less accurate in showing lineages in other areas of the world. If your roots were Asian or African, the reports were less likely to accurately reflect where your ancestors lived.

Over time, the data sets have improved and expanded, so consumers with non-European ancestry may get more accurate information about their heritages now than they would have previously. That trend will likely continue.

Whether DNA kits are mostly a gimmick, I cannot say. But it is important to recognize their limitations in providing trustworthy information about our health or ancestry. Certainly, we should not base health decisions on their results, and I would think twice about paying for the privilege of delivering my DNA profile to a for-profit company.

Maybe this year I’ll just give everyone tarot decks.

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

You can find Lynn on Twitter: @LynnRWebsterMD.

Opinions expressed here are those of the author alone and do not reflect the views or policy of PRA Health Sciences or Pain News Network. 

Genetic Variation Raises Risk of Post-Traumatic Pain

By Pat Anson, Editor

If you have chronic pain because of an accident, injury or assault, it could be because you have a genetic variation that makes you more likely to develop post-traumatic pain.

That’s the key finding behind a new study published in the Journal of Neuroscience. Researchers at the University of North Carolina studied over 1,500 people who were admitted to emergency rooms for trauma after a motor vehicle collision.

In addition to genotyping the patients, the researchers assessed their distress immediately after the accident, as well as their pain and post-traumatic stress symptoms six weeks later. Participants with a particular variant in the gene FKBP5 reported more severe pain and distress at follow up.

FKBP5 is a critical regulator of the stress response and affects how we respond to environmental stimuli. Previous studies have shown that certain variants of the gene play a role in the development of neuropsychiatric disorders such as post-traumatic stress disorder, depression, suicide risk and aggressive behavior.

UNC School of Medicine researchers were the first to show an association between FKBP5 and post-traumatic chronic pain. A 2013 study found that people with a particular variation of the gene are likely to experience more pain after exposure to trauma compared to people who don't have the variant.

The new study by the same research group builds on that discovery by showing that the variation inhibits the regulation of cortisol, a stress hormone that sensitizes peripheral nerves. People with high levels of cortisol are likely to experience more pain.

"In our current study, we showed that the reason this variant affects chronic pain outcomes is because it alters the ability of FKBP5 to be regulated by a microRNA called miR-320a," said lead author Sarah Linnstaedt, PhD, a professor of anesthesiology and an investigator in the UNC Institute for Trauma Recovery.

"In other words, it does not negatively regulate FKBP5, thus causing FKBP5 to be over-expressed. High levels of FKBP5 can be detrimental because it alters natural feedback mechanisms that control circulating cortisol levels."

Linnstaedt says the findings suggest there could be new therapeutic approaches to treating traumatic pain, such as medication that inhibits the activity of FKBP5 or gene editing that alters the variation.

Funding for the UNC study was provided by the National Institute of Arthritis, Musculoskeletal, and Skin Diseases, The Mayday Fund, a Future Leaders in Pain Grant from The American Pain Society, and the National Human Genome Research Institute.