- Published9 Aug 2019
Rina Diane Caballar
Felled by a splitting headache that has landed you in the doctor’s office, you now face an even more daunting task — describing it. Perhaps the pain is throbbing, maybe piercing, but every word seems inadequate and you can’t even pinpoint its source. What’s more, a nurse asks you to rate your pain on a scale of one to 10. Even then, a debilitating 10 headache for you may only rate a 4 for someone else.
Given its subjective nature, is it possible for doctors to verify pain severity? Alexander Niculescu at the Indiana University School of Medicine led a breakthrough study toward developing a first-of-its-kind blood test — an objective measure of pain that could lead to more accurate treatment.
What is pain, and how does it affect the body?
When you hit your toe against a door frame, you feel an aching sensation immediately. This is how pain begins, with the activation of nerve fibers called nociceptors located in joints, muscles, and skin. Nociceptors transmit pain signals from the spinal cord to the brain. The thalamus receives the signals and relays them to other regions including the somatosensory cortex, which helps determine pain severity and location, and the amygdala, which aids in processing the emotional aspect of pain. The brain then produces the actual conscious sensation of pain.
While we understand how the sensation spreads through our body, the problem lies in pain’s subjective nature. You may feel excruciating pain when you stub your toe, but someone else might shake it off easily. Doctors rely on patients’ reports of what they’re feeling to determine treatment. That’s why it’s so important to have objective measures of pain in the form of biomarkers.
What are the biomarkers for pain?
A biomarker is a biological measure of the presence or progress of a condition or disease. Biomarkers help doctors assess and diagnose patients, as well as monitor their response to treatment. Some examples of biomarkers include body temperature for fever, blood pressure for hypertension, and blood cholesterol for heart disease
In our case, the biomarkers were levels of gene expression in the blood. Gene expression is the process of creating functional gene products such as RNA and proteins — which are essential to cell functions — from the information in our DNA. The level of expression refers to the amount of functional gene product produced.
Our study tracked molecules — specifically ribonucleic acid or RNA — in the blood that changed in expression in relation to people’s perception of pain. First, we examined the molecules for each patient in our discovery cohort. We investigated changes in gene expression when patients were in a low pain state — pain rating of two or lower — and a high pain state — pain rating of six or higher.
We took our candidate biomarkers and cross-validated our findings with prior publications and other studies. In this way, we made sure they were reproducible and relevant.
Then, we tested the biomarkers that passed those steps in an independent group of patients with severe pain disorder to see whether our biomarkers changed even more.
Finally, we tested the remaining biomarkers in two additional independent cohorts. We wanted to see if our biomarkers could predict pain intensity and future pain-related visits to the emergency room.
After this careful approach, we had a small list of biomarkers: GNG7, CNTN1, LY9, CCDC144B, GBP1, and MFAP3. We found that GNG7 (G protein subunit gamma 7) is a strong predictor for future pain-related emergency room visits, while CNTN1 (contactin 1) is a strong predictor for pain intensity. In the study, pain intensity — a high pain state — is associated with a decreased expression of the gene, meaning CNTN1 is a pain suppressor gene.
How can doctors use these biomarkers to treat pain?
If you go into a cardiologist’s office complaining of chest pain, they don’t just rely on your description — they also do an electrocardiogram and blood test to verify whether you’re having a heart attack. Doctors can’t biopsy the brain to determine pain intensity, but they can use this blood test, which is where biomarkers come in.
In this blood test, doctors can draw a blood sample and test it for the presence of the biomarkers for pain. They’ll get a report with a list of possible medications for patients based on their biomarkers. Our studies have matched biomarkers to drugs or natural compounds that normalize their gene expression signature. The drug or natural compound match could be a treatment option, allowing doctors to match people to the right medication.
Using their clinical judgment, doctors can make a diagnosis and start people on a treatment that matches their biomarkers. They can do repeat blood tests to see how patients are responding to treatment.
Are these biomarkers universal?
We found some universal biomarkers — they identify pain regardless of gender or diagnosis. But we also found some that are better predictors in men and others that are better predictors in women. CNTN1 is linked to chronic pain in women, while LY9 (lymphocyte antigen 9) and MFAP3 are linked to post-traumatic stress disorder (PTSD) in men.
When you personalize by gender, you have better precision because men and women have different biological gene expression signatures.
Can these biomarkers help predict future experiences of chronic pain?
Some biomarkers are predictive of state, meaning they can identify if someone is in pain and pain severity at the time a blood sample is taken. Some are predictive of trait, meaning future pain-related emergency room visits months or years later. Those may indicate some predisposition to and chronicity of pain.
When they’re tested large-scale and we accumulate large databases of results, we could refine and understand biomarkers for specific disorders. Now, they’re used in any pain disorder, but in the future, there could be biomarkers for migraines, fibromyalgia, or many other disorders.
With a personalized approach — one that’s tailored to gender and diagnosis — we could achieve results even more accurate than universal biomarkers.
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