Pain Gene: Interesting, but Insufficient


Schematic of the SCN9A gene showing the position of known mutations (arrows) that result in human disorders of pain appreciation. SCN9A encodes the voltage-gated sodium channel, Nav1.7, which is composed of four repeating domains, each comprising six transmembrane segments. The regions of the gene that encode the transmembrane segments and the inactivation domain are indicated (see colored key). 


Reimann, Frank & Cox, James & Belfer, Inna & Diatchenko, Luda & Zaykin, Dmitri & Mchale, Duncan & Drenth, Joost & Dai, Feng & Wheeler, Jerry & Sanders, Frances & Wood, Linda & Wu, Tianxia & Karppinen, Jaro & Nikolajsen, Lone & Ruddock, Minna & Max, Mitchell & Kiselycznyk, Carly & Poddar, Minakshi & Morsche, Rene & Woods, C. (2010). Pain perception is altered by a nucleotide polymorphism in SCN9A. Proceedings of the National Academy of Sciences of the United States of America. 107. 5148-53. 10.1073/pnas.0913181107.


This article, in a slightly edited form, first appeared on Pain News Network on August 1, 2020.


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. 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 the inter-individual 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 a human’s experience 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. However the Neanderthal report 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.

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

You can find him on Twitter: @LynnRWebsterMD.


  1. Suzi on August 2, 2020 at 6:04 pm

    This is fascinating! From Neanderthals to the idea that life’s experiences contribute to our experience of pain. Never thought about this before. Great read.

  2. Jeffrey on August 4, 2020 at 1:03 am


Leave a Comment