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  • Michele Curatolo

How blood and urine metabolites could help understand chronic pain

Updated: Apr 12, 2022


This blog is a summary, in lay language, of our review on metabolomics in chronic pain, written in collaboration with Raftery's lab.

We urgently need to improve individualized chronic pain treatment

Chronic pain remains a leading cause of suffering and disability worldwide. Our very limited ability to provide effective treatments is largely the result of the limited understanding of pain mechanisms at individual level. Why do treatments work in some patients and not in other ones with the same condition? For instance, why do anti-seizure medication, such as pregabalin, work only in about one third of patients with fibromyalgia, if they all have the same diagnosis?

It important to realize that the current diagnostic criteria for chronic pain lump together patients with very different conditions and do not allow personalized medicine (learn more here). For instance, we call "fibromyalgia" the combination of symptom and signs of widespread pain. However, different patients with these manifestations may have different dysfunctions in their pain system that are not detected by conventional tests. Thus, we consider patients to have the same condition while they do not really have the same condition, and these difference contribute to different reactions to the same medication. As long as we are not able to detect these inter-individual differences, we will not be able to provide personalized medicine.

We need simple, inexpensive, clinically-applicable tools

In the last few decades, many efforts have been produced to develop methods to understand chronic pain in humans and improve personalized medicine. However, most of the methods investigated so far are demanding and expensive. For instance, advanced brain imaging studies have provide invaluable information on mechanisms of pain, but have not found the way to clinical use for personalized medicine. Important reasons, among others, are the limited benefit/cost ratio and difficult implementation on a large scale.

When searching for methods to understand pain at individual level, their implementation potential in the clinical settings is an essential consideration. Unless a test is extremely powerful, time and cost constraints will limit its applicability. The study of metabolites in blood and urine is a new field that, if validated by research, may fulfill the goal of large-scale clinical application.

What are metabolites, and what is metabolomics?

Metabolites are by-products of metabolic processes. Metabolomics is the identification and quantification of metabolites.

Metabolites are the products of a myriad of processes that occur both in normal conditions, and as a result of an illness. Therefore, measurement of metabolites may provide insights into the way the body functions, and inform us on dysfunctions related to pathological conditions.

Metabolites can be detected in blood and urine samples, and are therefore easily accessible and promising in terms of implementation potential in the clinical settings. Obviously, the question is whether measuring metabolites is useful at all.

Metabolomics for chronic pain is at its infancy

In our review, we have found only 19 studies that used metabolomics in chronic pain. Most of the studies have included only few patients. Because of the large number of potentially relevant metabolites, studies with very large number of patients are warranted.

Despite the limited available information, some consistency emerged from the analysis of the individual studies. One of them is glutamate metabolism. Glutamate is the primary excitatory neurotransmitter, meaning that it excites neurons and make them over-active. Neurons involved in pain generation and transmission amplify the pain signal when glutamate binds to their receptors. If confirmed by larger studies, glutamate metabolomics could help identify a patient-specific mechanisms for chronic pain and support the development and application of therapeutics.

A possible research pathway

When studying mechanisms in humans, one of the crucial questions is whether findings are relevant for patients' symptoms. Specifically, identifying an altered metabolite in patients with chronic pain does not necessarily imply that the metabolic pathway is involved in the chronic pain condition. To increase the chances that findings are relevant for patients, a number of steps are required, as illustrated in the figure below.

First, the clinical characterization of patients is of great importance ("phenotyping"). It is not enough to compare patients with chronic pain with healthy subjects, as this will lead to the identification of several metabolites of no relevance for pain. Conversely, adding measures of relevance to patients, such physical function or pain with touch ("allodynia"), will increase the chance to identify metabolites of relevance to the patient's problem.

Second, influencing the metabolic pathway with specific interventions, such as drugs, will confirm that the pathway identified in previous studies is pain-relevant. Without this information, the causal relationship between metabolites and pain would remain uncertain. In fact, a correlation between two measures (for example, a metabolite and pain intensity), does not necessarily imply that changes in pain result from changes in the metabolite. This step can also be accomplished with animal studies.

Finally, the identification of novel therapeutic targets would open the way to drug development for testing in clinical trials.

Possible research pathway to identify new treatments for chronic pain based on metabolomics, relying on advanced phenotyping and validation in animal models.
Possible research pathway to identify new treatments for chronic pain based on metabolomics

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