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.  

What Cavemen Used for Pain Relief

By Pat Anson, Editor

Neanderthals may be a lot smarter than we give them credit for. Especially when it comes to finding pain relief.

Ancient DNA extracted from the dental plaque of Neanderthals has revealed new insights into their behavior and diet, including their use of plant-based medicine to treat pain and illness.

An international team of researchers compared dental plaque from the jawbones of four Neanderthals found at ancient cave sites in Belgium (Spy Cave) and Spain (El Sidrón Cave). The four samples range from 42,000 to around 50,000 years old and are the oldest dental plaque ever to be genetically analyzed.

“Dental plaque traps microorganisms that lived in the mouth and pathogens found in the respiratory and gastrointestinal tract, as well as bits of food stuck in the teeth – preserving the DNA for thousands of years,” says Dr. Laura Weyrich, a research fellow at the University of Adelaide’s Australian Centre for Ancient DNA (ACAD), who was lead author of the groundbreaking study reported in the journal Nature.

RESEARCHERS IN EL SIDRON CAVE

“Genetic analysis of that DNA ‘locked-up’ in plaque, represents a unique window into Neanderthal lifestyle – revealing new details of what they ate, what their health was like and how the environment impacted their behavior.”

The researchers found that Neanderthals from Spy Cave were mostly meat eaters who consumed wooly rhinoceros and wild sheep, and supplemented their diet with wild mushrooms.

“Those from El Sidrón Cave on the other hand showed no evidence for meat consumption, but appeared instead to have a largely vegetarian diet, comprising pine nuts, moss, mushrooms and tree bark – showing quite different lifestyles between the two groups,” said professor Alan Cooper, Director of ACAD.

The analysis of one Neanderthal found at El Sidrón revealed another surprise. He probably had pain from a dental abscess on his jawbone, and also had signs of an intestinal parasite that causes acute diarrhea.

“Clearly he was quite sick. He was eating poplar, which contains the pain killer salicylic acid, and we could also detect a natural antibiotic mold not seen in the other specimens,” said Cooper. “Apparently, Neanderthals possessed a good knowledge of medicinal plants and their various anti-inflammatory and pain-relieving properties, and seem to be self-medicating.”

Salicylic acid is the active ingredient in aspirin; while certain types of mold – such as Penicillium – help the body fight off infections.

JAWBONE OF NEANDERTHAL FOUND IN EL SIDRON CAVE

“The use of antibiotics would be very surprising, as this is more than 40,000 years before we developed penicillin. Certainly our findings contrast markedly with the rather simplistic view of our ancient relatives in popular imagination,” says Cooper.

The researchers also found that Neanderthals and modern humans shared several disease-causing microbes, including the bacteria that cause dental cavities and gum disease.

Types of bacteria were closely associated with the amount of meat in the diet, with the Spanish Neanderthals grouping with ancient human ancestors in Africa. In contrast, the Belgian Neanderthal bacteria were similar to early hunter gatherers, and quite close to modern humans and early farmers.

“Not only can we now access direct evidence of what our ancestors were eating, but differences in diet and lifestyle also seem to be reflected in the commensal bacteria that lived in the mouths of both Neanderthals and modern humans,” said Professor Keith Dobney of the University of Liverpool.

“Major changes in what we eat have, however, significantly altered the balance of these microbial communities over thousands of years, which in turn continue to have fundamental consequences for our own health and well-being. This extraordinary window on the past is providing us with new ways to explore and understand our evolutionary history through the microorganisms that lived in us and with us.”