Genetics May Explain Why Women Are More Likely to Have Chronic Pain

By Pat Anson, PNN Editor

It’s no secret that women are far more likely than men to experience fibromyalgia, migraine, osteoarthritis and other chronic pain conditions. Why that is has been linked to everything from gender bias in healthcare to childhood trauma to women “catastrophizing” about their pain.  

A new study published by UK researchers in PLOS Genetics suggests that part of the reason is genetic differences between men and women.

In the largest genetic study of its kind, researchers at the University of Glasgow looked for genetic variants associated with chronic pain in over 209,000 women and 178,000 men who donated their medical and genetic data to the UK Biobank.

The researchers also investigated whether the activity of those genes was turned up or down in tissues commonly involved with chronic pain.

They found that 37 genes in men and 30 genes in women were active in the dorsal root ganglion, a cluster of nerves in the spinal cord that transmit pain signals from the body to the brain.

The findings support previous work by the same research team, which found that chronic pain originates to a large extent in the brain, and to a lesser degree in parts of the body where people “feel” pain. The study also suggests genetic differences between men and women may affect the immune system and how the two sexes respond to medication.

“Overall, our findings indicate the existence of potential sex differences in chronic pain at multiple levels… and the results support theories of strong nervous system and immune involvement in chronic pain in both sexes,” wrote lead author Keira Johnston of the University of Glasgow. "Our study highlights the importance of considering sex as a biological variable and showed subtle but interesting sex differences in the genetics of chronic pain."

Gender Bias

While genetic differences may partially explain why women are more likely to feel pain than men, gender biases may explain why they are treated differently, according to another study recently published in the Journal of Pain.

Researchers at the University of Miami found that when volunteers observed male and female patients expressing the same amount of pain, they had a tendency to view female patients' pain as less intense and more likely to benefit from psychotherapy.

The study consisted of two experiments in which adult volunteers were asked to view videos of men and women who suffered from shoulder pain. The videos came from a database of real patients experiencing different degrees of pain, and included their self-reported pain levels when moving their shoulders in a series of exercises.

The volunteer observers were asked to gauge the amount of pain they thought the patients in the videos experienced. They were also asked how much pain medication and psychotherapy they would prescribe to each patient, and which of the treatments they thought would be more effective.

The study found that female patients were perceived to be in less pain than the male patients — even when they reported and exhibited the same pain levels. Researchers believe those perceptions were partially explained by gender-based stereotypes.

"If the stereotype is to think women are more expressive than men, perhaps 'overly' expressive, then the tendency will be to discount women's pain behaviors," said co-author Elizabeth Losin, PhD, assistant professor of psychology at the University of Miami.

"The flip side of this stereotype is that men are perceived to be stoic, so when a man makes an intense pain facial expression, you think, 'Oh my, he must be dying!' The result of this gender stereotype about pain expression is that each unit of increased pain expression from a man is thought to represent a higher increase in his pain experience than that same increase in pain expression by a woman."

The volunteer observers were also more likely to choose psychotherapy as a treatment than pain medication for the female patients.

Interestingly, the gender of the observers did not influence pain estimation. Both men and women interpreted women's pain to be less intense.

"I think one critical piece of information that could be conveyed in medical curricula is that people, even those with medical training in other studies, have been found to have consistent demographic biases in how they assess the pain of male and female patients and that these biases impact treatment decisions," said Losin.

"Critically, our results demonstrate that these gender biases are not necessarily accurate. Women are not necessarily more expressive than men, and thus their pain expression should not be discounted."

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

Is Chronic Pain a Family Affair?

By Pat Anson, Editor

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

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

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

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

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

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

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

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

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

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

Poor Fitness Leads to Childhood Pain

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

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

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