Medical Policy

This document addresses analysis of urine biomarkers for the management of chronic pain.

Note: This document does not address drug testing for chronic pain. For more information, please see the following related document:

• CG-LAB-09 Drug Testing or Screening in the Context of Substance Use Disorder and Chronic Pain

Note: For a high-level overview of this document, please see "Summary for Members and Families" below.

Investigational and Not Medically Necessary:

Analysis of urine biomarkers to assess chronic pain is considered investigational and not medically necessary for all indications.

This document describes clinical studies and expert recommendations, and explains why we consider the analysis of urine biomarkers for the management of chronic pain not clinically appropriate. The following summary does not replace the not medically necessary statement or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

Some labs have made urine tests that look at chemicals in the body to help in the detection and management of a variety of health conditions, including pain. These chemicals are called biomarkers. The tests check whether the levels of these chemicals are higher or lower than normal. One test proposed to help with the treatment of pain is called the Foundation Pain Index (FPI, Ethos Laboratories, Newport, KY), which looks at 11 chemicals in a urine sample and gives a score meant to show whether a person’s pain-related biomarker levels are higher than normal.

This test is not the same as a urine drug test. A drug test checks whether a person is taking medicines as prescribed. The Foundation Pain Index looks at natural chemicals made by the body linked to the presence of pain, swelling, and nerve health.

What Does the Research Say?

The research on such tests is limited and still in its early stages. The main study done on the Foundation Pain Index looked at urine from a large group of people with long-term pain. It found that many had at least one chemical outside the normal range. But the study did not rule out other causes for those results, such as other health issues or medicines.

Two newer studies looked at some of the same chemicals in a small group of active-duty service members with long-term pain. They found only weak links between the chemicals and how people rated their pain and daily life. The differences detected by the tests in these studies were so small they may not matter in real care. Neither study evaluated whether using the test helped doctors make better choices or helped people feel better.

No study has shown this test leads to better care or health. Better studies are needed to know if this type of test helps people with long-term pain. Using a test before benefit is proven may affect care decisions without improving health.

What Is Clinically Appropriate?

These types of tests are not considered appropriate for care at this time because their use has not been shown to improve people’s health.

The studies so far are too small and in early stages. Most were done by the company that sells the test. No major medical group recommends the use of such tests. Use of an unproven test may lead to unnecessary care or harm.

(Return to Description/Scope)

Summary

At this time there is only one test available on the market in the U.S. that is proposed for the measurement of biomarkers for the management of pain. The Foundation Pain Index (FPI, Ethos Laboratories, Newport, KY) is a proprietary 11-analyte urine biomarker panel developed by a single laboratory and proposed for use in chronic pain assessment. However, research to date has not established its clinical validity or utility. The existing evidence base consists primarily of manufacturer-sponsored observational studies demonstrating that individuals with chronic pain exhibit higher rates of abnormal biomarker findings, though the clinical significance of these associations remains unclear. Independent research has identified weak statistical associations between select urine metabolites and self-reported pain outcomes in military populations, but these exploratory analyses have not demonstrated that testing changes clinical decision-making or improves outcomes. No professional medical society has endorsed urine biomarker testing for chronic pain management, and no federal regulatory body has cleared or approved a proprietary urine biomarker panel for this indication.

Discussion

Test Description and Analytical Framework

Chronic pain biomarker research remains an active area of investigation, though no validated diagnostic biomarker for chronic pain has been established (Reckziegel, 2019). Ethos Laboratories developed the Foundation Pain Index (FPI), a proprietary analysis of urine biomarkers for pain. The test utilizes liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze urine samples for 11 endogenous analytes: methylmalonic acid, xanthurenic acid, homocysteine, pyroglutamic acid, vanilmandelate, 5-hydroxyindoleacetic acid, hydroxymethylglutarate, ethylmalonate, 3-hydroxypropyl mercapturic acid (3-HPMA), quinolinic acid, and kynurenic acid. These substances are proposed to serve as markers of chronic inflammation, nerve health, neurotransmitter status, and oxidative stress. Algorithmic analysis of these analytes generates a composite Pain Index Score intended to indicate the likelihood of atypical biochemical function associated with pain. The FPI operates as a laboratory-developed test with no U.S. Food and Drug Administration (FDA) clearance or approval, and Ethos Laboratories is the sole-source provider. The test is billed under Current Procedural Terminology (CPT) code 0117U.

Prevalence of Biomarker Abnormalities in Chronic Pain

A retrospective observational study evaluated the prevalence of abnormal biomarker findings among 17,834 individuals with chronic pain whose urine samples were analyzed at Ethos Laboratories (Gunn, 2020). The investigators reported that 77% of individuals with chronic pain exhibited at least one abnormal pain biomarker result (n=13,765), compared to up to 5% of healthy persons with no history of chronic pain or opioid use. The most common abnormal finding was elevated quinolinic acid, observed in 29% of participants (n=5107). Elevated pyroglutamate, indicative of glutathione depletion, was observed in 19% (n=3314). Elevated xanthurenic acid, indicative of vitamin B6 insufficiency, was observed in 17% (n=3025). Elevated levels of the acrolein metabolite 3-hydroxypropyl mercapturic acid (3-HPMA) were observed in 21% (n=3667). Elevated methylmalonic acid, indicative of vitamin B12 deficiency, was observed in 10% (n=1827), and abnormally low levels of neurotransmitter metabolites were observed in 8% (n=1456). The investigators acknowledged that medications and conditions other than those associated with chronic pain were not evaluated as potential causes of abnormal biomarker findings. This single-center retrospective study, conducted at the test manufacturer’s own laboratory, represents the primary prevalence data for the Foundation Pain Index (FPI). No independent replication of these findings has been published.

Manufacturer-Sponsored Validation Studies

Subsequent studies from investigators affiliated with Ethos Laboratories sought to establish clinical validity for the Foundation Pain Index (FPI). A cross-sectional, observational study evaluated associations between FPI biomarker levels and clinical pain measures in individuals with chronic pain (Amirdelfan, 2020). A cross-validation analysis compared FPI results against the Patient-Reported Outcomes Measurement Information System 29-item profile in a chronic pain population (Pope, 2021). Both studies reported statistically significant associations between certain biomarker abnormalities and self-reported pain domains; however, neither study employed a randomized controlled design, both relied on convenience samples, and the investigators had financial relationships with the test manufacturer. Critically, neither study evaluated whether FPI-guided management altered treatment decisions or improved clinical outcomes compared to standard care alone.

Independent Research on Urine Metabolites and Pain Outcomes

Two investigations conducted independently of Ethos Laboratories examined a related but distinct set of urine metabolites in a military chronic pain population. A secondary analysis of data from a pragmatic clinical trial (ClinicalTrials.gov identifier NCT03297905) involving 169 active-duty service members with chronic pain at Madigan Army Medical Center was conducted (Wi, 2025). The investigators analyzed a four-metabolite urine composite termed the Urine Metabolite Pain Indicator (UMPI), comprising kynurenic acid, pyroglutamic acid, ethylmalonic acid, and methylmalonate. Three of these four metabolites overlap with analytes in the Foundation Pain Index (FPI) panel. Cross-sectional analysis revealed statistically significant associations between the UMPI and 5 of 11 self-reported outcomes, including fatigue, anxiety, depression, physical functioning, and overall pain impact; however, adjusted Pearson correlations were weak, ranging from 0.18 to 0.25. The composite demonstrated modest internal reliability (Cronbach’s alpha=0.61). Given the study’s small sample size and exploratory nature, a relaxed significance threshold of p less than or equal to 0.10 was used for all analyses.

A longitudinal extension examined whether UMPI associations persisted at 6-week follow-up in 148 active-duty service members from the same trial who received either complementary and integrative health therapies or standard rehabilitative care (Wi, 2026). The UMPI remained associated with physical function and overall pain impact post-intervention, with unadjusted correlations of 0.17 to 0.20. Ethylmalonic acid showed associations with fatigue, anger, and physical function. Methylmalonate, while not significant at baseline, demonstrated the most robust post-intervention associations. The authors acknowledged several limitations, including a modest sample size, a population consisting primarily of individuals with musculoskeletal pain, a short follow-up period (6 weeks), and the need for replication in civilian populations with broader comorbidity profiles. Neither study evaluated whether urine metabolite testing changed clinical decision-making or improved treatment outcomes.

Evidence for Clinical Utility

A review examined the extent to which current laboratory biomarkers inform clinical decision-making in chronic pain management (Hagedorn, 2021). Across the available literature, no study has demonstrated that urine biomarker testing for chronic pain, whether via the Foundation Pain Index (FPI) or comparable panels, changes treatment decisions or improves clinical outcomes relative to standard care. The distinction between clinical validity (whether a test measures what it claims to measure) and clinical utility (whether a test improves clinical outcomes when used to guide management) is central to coverage determinations for diagnostic tests. While the studies summarized above provide preliminary evidence of statistical associations between certain urine metabolites and self-reported pain measures, the effect sizes are uniformly weak, the study designs are observational or exploratory, and no trial has randomized individuals to management guided by biomarker testing versus standard assessment alone. Ethos Laboratories has stated that the FPI provides personalized recommendations for adjunctive therapy based on test results, but no published evidence supports a causal link between FPI-guided recommendations and improved pain outcomes.

Professional Society Guidelines

No major professional medical society, including the American Academy of Pain Medicine (AAPM), the American Society of Interventional Pain Physicians (ASIPP), or the International Association for the Study of Pain (IASP), has issued guidelines or position statements endorsing urine biomarker analysis for chronic pain management.

Other Relevant Information
No Food and Drug Administration (FDA)-labeled indications have been identified for the tests that analyze urine biomarkers for the management of chronic pain. According to the Centers for Medicare & Medicaid Services (CMS) Local Coverage Determination (LCD) L39616, titled Urinary Biomarkers for Chronic Pain Management, “Currently there is not established evidence to support a role of urinary biomarkers for management of chronic pain, therefore CGS Administrators consider urinary biomarker test for chronic pain experimental and non-covered.”

Commercially available tests for analysis of urine biomarkers for the management of chronic, functional pain include the Foundation Pain Index (FPI) (previously referred to as PI^℠). The FPI is intended for use in adults being treated for chronic pain when the treating clinician is attempting to determine the underlying pathogenesis of the pain, attempting to minimize or lower opioid dependence, or wanting to identify targeted, non-opioid therapies for the individual. Specifically, individuals with chronic pain of unknown etiology, new individuals presenting with pain, and those with established chronic pain diagnoses being managed on opioid therapy represent the intended use population for FPI. An algorithm is then reported as a Pain Index Score with a projected likelihood of atypical biochemical function associated with pain. Ethos Laboratories claims that individual test results, both current and historic, could potentially enable clinicians to identify changes in an individual’s functional biomarkers over time and in response to treatment.

Functional pain: Symptoms of pain associated with no obvious organic origin.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS): An analytical tool that is based on coupling mass spectrometers together in a series to analyze complex mixtures. Historically, LC-MS/MS has been used primarily by research, pharmaceutical, or commercial laboratories. Recent advances in the technology, decreasing costs for basic systems, user-friendly software, an increased number of published protocols and methods, and the release of Food and Drug Administration (FDA)-approved kits have enabled more clinical laboratories to pursue these instruments as viable clinical analyzers.

Mass spectrometry: An analytical tool useful for measuring the mass-to-charge ratio (m/z) of one or more molecules present in a sample. Mass spectrometers can be used to identify unknown compounds via molecular weight determination, to quantify known compounds, and to determine structure and chemical properties of molecules.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
For the following procedure code, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer-Reviewed Publications:

1. Amirdelfan K, Pope JE, Gunn J, et al. Clinical validation of a multi-biomarker assay for the evaluation of chronic pain patients in a cross-sectional, observational study. Pain Ther. 2020; 9(2):511-529.
2. Gunn J, Hill MM, Cotten BM, Deer TR. An analysis of biomarkers in patients with chronic pain. Pain Physician. 2020; 23(1):E41-E49.
3. Hagedorn JM, Gunn J, Budwany R, et al. How well do current laboratory biomarkers inform clinical decision-making in chronic pain management? J Pain Res. 2021; 14:3695-3710.
4. Pope JE, Fishman MA, Gunn JA, et al. Cross-validation of the Foundation Pain Index with PROMIS-29 in chronic pain patients. J Pain Res. 2021; 14:2677-2685.
5. Reckziegel D, Vachon-Presseau E, Petre B, et al. Deconstructing biomarkers for chronic pain: context- and hypothesis-dependent biomarker types in relation to chronic pain. Pain. 2019; 160(Suppl 1):S37-S48.
6. Wi D, Choi H, Tintle N, et al. Urine metabolites as indicators of chronic pain and related symptoms in active-duty service members: a secondary data analysis of a pragmatic clinical trial with SMART design. Nurs Res. 2025; 74(4):272-279.
7. Wi D, Flynn DM, Tintle N, et al. Post-treatment urine metabolites as indicators of chronic pain: a secondary data analysis of a pragmatic clinical trial. Biol Res Nurs. 2026; 28(1):40-49.

Government Agency, Medical Society, and Other Authoritative Publications:

1. CGS Administrators, LLC. Jurisdiction J-15. Local Coverage Determination: Urinary Biomarkers for Chronic Pain Management (L39616). Effective 01/22/2026. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdId=39616&ver=5. Accessed on May 15, 2026.

Foundation Pain Index
Foundation PI^℠
FPI

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

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