Editor’s Note: At the 2018 World Congress on Pain in Boston, the biennial meeting of the International Association for the Study of Pain (IASP), researchers from around the world gathered from September 12-16 to discuss the latest pain research. Twelve young scientists attending the World Congress were selected to provide first-hand reporting from the event, as part of the PRF Correspondents program, which is a science communications training program provided by the Pain Research Forum, RELIEF’s parent site. Here, PRF Correspondent Tayler Sheahan, PhD, a postdoctoral research fellow at the University of Pittsburgh, US, reports on a plenary lecture delivered at the meeting by David Bennett, a professor of neurology and neurobiology at the University of Oxford in the UK. (RELIEF’s news coverage is editorially independent of its publisher, IASP. All editorial decisions about our reporting on IASP activities are made solely by the RELIEF editors).
Many people who know someone suffering from chronic pain may be familiar with this narrative: A family member—let’s say a sister or an aunt—has severe chronic pain that’s interfering with her life. She goes to the doctor, who prescribes gabapentin, a drug often used for chronic pain. That doesn’t help, so she goes back to the doctor, who this time prescribes amitriptyline, a drug also used for pain but that works in a different way. That doesn’t help either. And so on, and so on, and so on…
This scenario is especially common for patients experiencing neuropathic pain, which is pain resulting from nerve injury. Failure rates for frequently prescribed medicines reach 70% for certain types of neuropathic pain conditions. Why is this the case, and what are researchers and doctors doing about it? This was the focus of a talk at the 2018 World Congress on Pain by David Bennett, a professor and pain researcher at the University of Oxford.
The message of his talk was that patients with neuropathic pain are not all the same, and doctors and researchers now appreciate the need to treat the patient, rather than the pain condition. With new and improved approaches for identifying subgroups of neuropathic pain patients, the future looks bright for more effective treatments.
Neuropathic pain is not a “one size fits all” condition
Historically, neuropathic pain has been difficult to diagnose—and, in turn, to treat—because it isn’t a “one size fits all” condition. Neuropathic pain is caused by damage to the nervous system, whether it be from an external injury, as is the case with phantom limb pain and spinal cord injury, from disease, or even from medical treatments. For instance, people with diabetes often suffer pain from neuropathic pain (diabetic neuropathy), as do those receiving chemotherapy treatment for cancer (chemotherapy-induced neuropathy).
The constellation of symptoms, or “pain profiles,” characteristic of patients with neuropathic pain conditions are as diverse as the causes. For instance, some diabetic neuropathy patients experience heightened pain in response to harmless heat or touch, while others experience a loss of sensation. This wide variety of symptoms reinforces the idea that people with neuropathic pain aren’t all the same.
Nevertheless, until recently, doctors overlooked pain profiles and instead focused on the injury that caused the pain, as well as the location of the pain. Treatment approaches have also been less than ideal, based on the personal experience of the doctor, and not necessarily on what’s known as “evidence-based medicine,” which refers to when doctors make healthcare decisions for their patients based on solid research studies. What’s more, why pain profiles can differ between patients is not fully understood.
Having recognized this crucial gap in knowledge, Bennett and others are working to improve the understanding, diagnosis, and ultimately treatment of neuropathic pain. The approach? Patient stratification.
Divide and conquer
Patient stratification is the process of identifying subgroups of patients who suffer from a disorder, with the goal of better matching patients to treatments. Stratified medicine is one step below personalized medicine, which aims to optimize treatment for individual patients based in part on their genetic makeup, as is the case with cancer vaccines and stem cell therapies. In the context of neuropathic pain, a stratified patient subgroup might include patients who share the same source of pain, such as diabetic neuropathy, or the same pain profile, such as heightened pain in response to heat.
The idea of patient stratification for the diagnosis and treatment of chronic pain is not new. However, figuring out how to stratify patients for improved pain treatment has been difficult because of a lack of effective tools to do so. Bennett and his colleagues have recently evaluated a variety of new tools for the stratification of neuropathic pain patients. One way to think about these tools in the context of pain from nerve injury is in terms of the “5 Ws”: Who, What, Where, When, and Why.
Who is more likely to be affected by pain conditions?
One of the most basic methods of patient stratification is to divide patients by sex. Chronic pain conditions are more prevalent in women than in men worldwide. One theory for this is that it is more socially acceptable for women to express their pain than men, and so women are more likely to go see a doctor and report their pain.
However, researchers have also identified important biological differences between males and females, such as stress and immune system responses to pain, which might underlie sex differences in the risk for chronic pain. This remains an active area of investigation in the pain field.
Smaller research studies also indicate that age, race and ethnicity, as well as income and education level, all influence the risk for developing chronic pain. Larger, more comprehensive investigations are required to uncover which patient subgroups are most vulnerable.
What are the defining characteristics of the pain?
Another approach is to stratify neuropathic pain patients by their pain profile. Pain profiles can be determined in a number of ways. Screening questionnaires are used to gather patient self-reports on the quality of pain. Typical questions may include, “Does your pain feel like burning, squeezing, or stabbing?” and “Is your pain increased by contact with cold or pressure?” Such questionnaires are easy to implement and can be collected from large patient groups.
Doctors and researchers can also determine a patient’s pain profile directly by measuring sensitivity to heat, cold, and touch. This is known as quantitative sensory testing, or QST. While quantitative sensory testing provides more standardized data on pain profiles, it requires far greater time and resources, including testing equipment.
Interestingly, the three pain profiles seen in patients with diabetic neuropathy—heightened pain in response to heat, heightened pain in response to touch, or loss of sensation—are found in patients with different neuropathic pain conditions. This means that diabetic neuropathy, and, say, postherpetic neuralgia (nerve pain caused by shingles, which results from reactivation of the virus that causes chicken pox) somehow manifest in similar symptoms.
Therefore, it may be more relevant to stratify and treat patients based on their pain profile, rather than by the initial event or injury that led to pain. Bennett also said that studying the commonalities in pain profiles between different neuropathic pain conditions could provide new insight into the underlying mechanisms of neuropathic pain, that is, the processes that go on at a cellular and molecular level in the nervous system.
Where in the nervous system have changes occurred?
Neuropathic pain patients can also be grouped based on where within the nervous system changes have occurred. For example, neuropathic pain can result from alterations in the peripheral nervous system (nerve fibers that extend from the spinal cord to the skin and internal organs) or the central nervous system (brain and spinal cord).
One technique for measuring peripheral nervous system function is called microneurography. This involves recording the electrical activity of individual nerve fibers that run from the skin to the spinal cord. Increased activity of these fibers is thought to be a driver of neuropathic pain and has been associated with neuropathic pain conditions such as diabetic neuropathy.
Brain imaging techniques such as functional magnetic resonance imaging (fMRI) can be used in neuropathic pain patients to detect changes in activity in specific regions of the brain. One region of particular interest to pain researchers is the periaqueductal gray, which can amplify or dampen pain. fMRI studies suggest that in some patients with neuropathic pain, the periaqueductal gray amplifies pain too much, which may play a role in their ongoing pain.
When are patients at higher risk for developing neuropathic pain?
Bennett also said that assessing stress, anxiety, and depression may be a useful way to stratify neuropathic pain patients. Chronic pain conditions of all kinds are known to interrupt many aspects of daily life, making it more difficult to do work, enjoy hobbies, and even sleep, with 40-50% of chronic pain patients having mood disorders.
How might mental health directly or indirectly influence pain conditions? One idea is that poor mental health is an obstacle to sticking to prescribed medication regimens, as well as to making lifestyle changes that would improve pain, such as exercising and eating healthy.
How stress, anxiety, and depression influence neuropathic pain in particular has yet to be explored. But once the relationship between neuropathic pain and mental health is better understood, clinicians will be able to develop pain management programs with a patient’s mental health condition in mind.
Why are some people at greater genetic risk for neuropathic pain?
Genetic sequencing is an approach for patient stratification across medical fields, and pain is no exception. For instance, by studying the genetic makeup of families with rare pain disorders, researchers have identified some of the genes that underlie neuropathic pain.
A gene that has particularly caught the eye of pain researchers who study neuropathic pain disorders is called SCN9A. This gene provides the instructions to make an ion channel, which is a protein that can be thought of as a control dial for pain nerve fiber activity.
People with a mutation that enhances SCN9A function develop severe chronic pain, whereas individuals with a mutation that impairs SCN9A function feel no pain at all. In the case of more subtle mutations, an individual with a mutation that mildly enhances SCN9A function might not typically have pain symptoms but may have a higher risk of developing neuropathic pain if suffering from another disease, such as diabetes.
Genetic sequencing undoubtedly represents a powerful tool for the diagnosis of neuropathic pain. Moreover, taking a patient’s genetic makeup into account is a promising approach for improving neuropathic pain treatment plans. However, a number of hurdles must be overcome before genetic sequencing can be widely used as a tool for patient stratification. For instance, a change in a gene such as SCN9A that’s linked to the development of neuropathic pain doesn’t always mean that the protein the gene makes will function poorly.
To understand which gene variations warrant medical concern, a very large population—several hundreds of thousands of people—with and without chronic pain will first need to undergo genetic sequencing to understand which variations result in altered pain profiles. Other concerns surrounding genetic sequencing include how to keep a person’s genetic information private, as well as the most ethical way for researchers to share genetic information with other researchers so they can do additional studies.
Using the right tools for the job
Tools for neuropathic pain patient stratification truly run the gamut. That patients can be grouped based on differences in their genes, all the way to differences in their mental health, highlights the complexity of neuropathic pain conditions. There is still much to learn about which stratification tool—or more likely combination of tools—is right for the job.
Researchers like Bennett are confident that stratified medicine already has, and will continue to, improve the understanding, diagnosis, and treatment of neuropathic pain. Stratification promises to reveal subgroups of patients who benefit from a therapy—this is a gain that might otherwise be masked when considering patients as one large, homogenous group. The ultimate hope for stratification is that it will allow doctors to select an effective treatment the first time the patient visits the clinic. When one size no longer fits all, a better path to pain relief emerges.
Tayler Sheahan, PhD, is a postdoctoral research fellow at the University of Pittsburgh, US.