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 see:

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

Investigational and Not Medically Necessary:

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

Ethos Laboratories (Newport, KY), in partnership with Ethos R&D, developed the Foundation Pain Index (FPI), a proprietary analysis of urine biomarkers for pain. The test utilizes liquid chromatography tandem mass spectrometry (LCM/MS) to analyze urine samples for 11 endogenous analytes. Specifically, methylmalonic acid, xanthurenic acid, homocysteine, pyroglutamic acid, vanilmandelate, 5-hydroxyindoleacetic acid, hydroxymethylglutarate, ethylmalonate, 3-hydroxypropyl mercapturic acid (3-HPMA), quinolinic acid, kynurenic acid, which are urine biomarkers known to be associated with pain and proposed to be used as part of a pain-specific work-up. Pain biomarker assessment provides insight into the possible origins of neuropathic pain, inflammatory pain, and altered pain perception. The analytes included in this functional biomarker testing can be classified as markers of the following:

• Chronic inflammation;
• Nerve health;
• Neurotransmitter status;
• Oxidative stress.

Ethos laboratories has based its efficacy on a single retrospective observational study of 17,834 participants with chronic pain. Results claim that 77% of these participants with chronic pain exhibited at least one abnormal pain biomarker. In contrast, among healthy people with no history of chronic pain or opioid use, only up to 5% exhibited one or more of these abnormal biomarkers. The most common abnormal biomarker finding was elevated quinolinic acid, which was observed in 29% of participants (n=5107). Elevated pyroglutamate, indicative of glutathione depletion, was observed in 19% of participants (n=3314). Elevated xanthurenic acid, indicative of vitamin B6 insufficiency, was observed in 17% of participants (n=3025). Elevated levels of the acrolein metabolite 3-hydroxypropyl mercapturic acid was observed in 21% of participants (n=3667). Elevated methylmalonic acid, indicative of a vitamin B12 deficiency, was observed in 10% of participants (n=1827), whereas abnormally low levels of neurotransmitter metabolites were observed in 8% of participants (n=1456). The investigators noted that a limitation of this study was that medications and conditions other than those associated with chronic pain were not evaluated as potential causes of abnormal biomarker findings (Gunn, 2020).

There is a lack of evidence in the peer-reviewed published medical literature of the clinical validity and utility of this test. Ethos laboratories also claims the ability to provide personalized recommendations for adjunctive therapy based on the test results, “Uncovering the biochemical origins of a patient’s chronic pain can suggest relevant, personalized treatment approaches.” However, further study with large, well-designed trials are needed to elucidate the true value of these test findings, as it relates to conventional pain management strategies.

Other Relevant Information

No FDA labeled indications have been identified for the tests that conduct analysis of 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.” No nationally recognized clinical practice guidelines currently address analysis of urine biomarkers for pain management.

Commercially available tests for analysis of urine biomarkers for the management of chronic, functional pain includes the 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 (PIS) with projected likelihood of atypical biochemical function associated with pain. Ethos laboratories claims that individual test results, both current and historic, would potentially enable providers 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.

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.

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

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. Sun AL, Ni YH, Li XB, et al. Urinary methylmalonic acid as an indicator of early vitamin B12 deficiency and its role in polyneuropathy in type 2 diabetes. J Diabetes Res. 2014; 2014:1-6.

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 10/08/2023. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdId=39616&ver=4. Accessed on May 14, 2024.

Foundation PI^℠

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.