Urinary Biomarkers for Chronic Pain Management

Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

Title XVIII of the Social Security Act, §1862(a)(1)(D) Investigational or Experimental

42 Code of Federal Regulations (CFR) §410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests

CMS Internet-Only Manuals, Pub 100-02, Medicare Benefit Policy Manual, Chapter 15, §80.1.2 A/B MAC (B) Contacts With Independent Clinical Laboratories.

CMS Internet-Only Manual, Pub. 100-04, Medicare Claims Processing Manual, Chapter 16, §50.5 Jurisdiction of Laboratory Claims.

For this policy: Urinary biomarker laboratory tests for chronic pain are non-covered by this contractor.

Background

Chronic pain is a significant problem that is complex and challenging to treat. The mechanisms of chronic pain are not well understood, and the lack of objective diagnostic tests adds to this challenge. Research to develop biomarkers for chronic pain is of interest as this may provide guidance for drug development and clinical practice. A biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathological processes or pharmacological responses to a therapeutic intervention” (Biomarker Definitions Working Group, 2001).¹ Biomarkers aim to help diagnose, aid in prognosis and evaluation of treatment responses and can inform rational drug development. There are no specific biomarkers for chronic pain.¹

Commercially available at the time of this LCD includes a novel, pain algorithmic based biomarker test panel called Foundation Pain Index (FPI) was developed by Ethos Laboratories, Newport, KY to evaluate biomarkers of systemic inflammation, oxidative stress, neurotransmitter turnover, and micronutrient status. The test includes analysis of 11 endogenous analytes (methylmalonic acid, xanthurenic acid, homocysteine, pyroglutamic acid, vanilmandelate, 5- hydroxyindoleacetic acid, hydroxymethylglutarate, ethylmalonate, 3- hydroxypropyl mercapturic acid (3- HPMA), quinolinic acid, kynurenic acid), LC- MS/MS collected via urine sample. An algorithm is used to report a pain-index score with likelihood of atypical biochemical function associated with pain. The concept is based on emerging research that nutrition-based interventions could reduce the severity and intensity of pain and that nearly all neurogenerative diseases appear to have an underlying diet-induced, pro-inflammatory state that can be mitigated if diagnosed.²

Literature search from PubMed, Google Scholar, Google, ClinicalTrials.gov, EBSCO Host with search words “chronic pain, pain biomarker OR oxidative stress” included 196 articles. Three systematic reviews, 9 RCTs and 186 other papers and 11 citations added manually due to abstraction from bibliography were reviewed. The majority consistent of case reports, series, review papers and small cohorts. The LCD review was limited to cohort studies with >25 subjects and randomized controlled studies (RCT). If a paper was investigating a biomarker for pain management that was not one of the 11 analytes included in the FPI lab it was reviewed, but not added to evidence review.

Biomarkers for Chronic Pain

Randomized controlled trails identified in literature search as described above were reviewed for evidence to support the role of specific biomarkers for pain. Multiple small RCTs investigated a wide variety of biomarkers, but these reports all had inadequate sample sizes (<25 in study arm for all reports reviewed) to determine if there is a relation. None of the reports investigated the same biomarkers measured with the FPI test so were not added to the LCD.

A 2021 narrative review was conducted to assess the literature regarding the use of laboratory biomarkers in chronic pain. A total of 304 manuscripts were produced from PubMed, Science Direct, and Google Scholar databases. Ultimately 75 manuscripts were included. Authors concluded that biomarkers, including urinary, serum, cerebrospinal fluid, and salivary, may be helpful in identifying patients at risk of developing disease and may help predict disease progression and assist with plan of treatment. They go further to state “additional research is necessary before specific recommendations can be made, and current clinical decision-making is modified”.³ Two/three authors of this paper have conflicts of interest due to relationship with Ethos Laboratories.

A 2020 systematic review on the metabolomics of chronic pain conditions reviewed published studies that used various metabolomic approaches to investigate chronic pain conditions among subjects of all ages. A total of 586 articles are identified and 18 included in the review that included fibromyalgia (n= 5), osteoarthritis (n=4), migraine (n=3), musculoskeletal pain (n=2), and other chronic pain conditions (n=1). The authors looked at several metabolites including amino acids (e.g., glutamine, serine, and phenylalanine) and intermediate products (e.g., succinate, citrate, acetylcarnitine, and Nacetylornithine) of pathways that metabolize various macromolecules. The authors conclude that despite the increase in research few metabolites have been validated as biomarkers for pain management. Preliminary evidence supports that there may be a role for these markers, and they call for a need for further investigation as this could be a potentially useful pathway to help in management of these conditions. They conclude “Alterations in the intermediate metabolites of carbohydrates, proteins, and other macromolecules are associated with chronic pain conditions such as fibromyalgia, osteoarthritis, and migraine. Unfortunately, many studies in the present review did not quantify the amount of pain experienced by participants. Further investigations are warranted to identify complete metabolomic profiles of various chronic pain conditions. Also, studies are needed to examine whether multiple metabolomic profiles correlate with pain outcomes such as pain severity and quality of life. These studies may lead to the identification of biomarkers and individualized strategies for the prevention, diagnosis, and management of chronic pain. Nurse scientists and other investigators should consider using standardized measurements to phenotype pain to facilitate comparisons across pain conditions and patient populations.”⁴

Lifestyle Modification and Nutritional Treatments for Pain

The basis of the FPI test is that there are nutritional deficiencies, metabolic abnormalities, and oxidative stress that can be treated by dietary modifications or supplementation. The concept of lifestyle and nutrition in pain has been explored. Several complementary medicine options ranging from non-pharmaceutical (such as Chinese medicine acupuncture, specialized diets), dietary supplements and other modalities have been explored but the mechanism of these pathways are not clear, and interventions not supported by high-quality evidence.

The Agency of Healthcare Research and Quality conducted a systematic review which included 185 RCTs in 221 publications and 5 systematic reviews on nonopioid pharmacologic agents in patients with chronic pain. Meta-analyses were conducted where data allowed. The authors concluded small improvements in pain and/or function with serotonin-norepinephrine reuptake inhibitor antidepressants for neuropathic pain, fibromyalgia, osteoarthritis and low back pain; pregabalin/gabapentin for neuropathic pain and fibromyalgia; oxcarbazepine for neuropathic pain; and NSAIDs for osteoarthritis and inflammatory arthritis. Other drugs studied, including acetaminophen (osteoarthritis), capsaicin (neuropathic pain), cannabis (neuropathic pain), amitriptyline (fibromyalgia, neuropathic pain), and cyclobenzaprine (fibromyalgia) had no clear effects. While supplements were not included in this report, they we're not excluded from the literature search and did not come up as part of the standard management for chronic pain conditions.⁵

Up To Date supports recommendation for healthy dietary changes and overall health benefit of general health and fitness. Treatment with specific nutritional modification is not included in chronic non-cancer pain in adult.⁶

Foundational Pain Index (FPI)

A 2020 retrospective observational study to determine and evaluate the prevalence of abnormal biomarker findings in a population of patients with chronic pain reports on data collected at a single industry site (Ethos Research & Development, Newport, KY) from clinical samples collected and analyzed from July to December 2018. A total of 17,834 unique patient samples were analyzed and abnormal was defined as being outside of the 95% confidence interval reference range established using healthy population of donors who had no history of chronic pain or opioid use. The authors reported that at least one abnormal biomarker was exhibited in 77% (n= 13,765) of chronic pain patients. The authors conclude that this novel biomarker assay reveals high prevalence of atypical biochemistry in the chronic pain population and can play a role in personalized pain management.⁷ Limitations to this study include the retrospective observational design, confounding due to medications and/or conditions other than those associated with chronic pain were not evaluated as potential causes of abnormal biomarker findings and risk of bias as the study was funded by Ethos. The authors conclude this panel can indicate novel, safe, and cost-effective pain treatments, but the treatment of pain and outcomes were beyond the scope of this retrospective review. Additionally, the role of the individual biomarkers in chronic pain is not clearly established and there are not specific biomarkers for chronic pain.^1,5

A 2020 cross-sectional observational study was conducted to validate the FPI as an indicator of abnormal biochemical function in a chronic pain population. This report, developed by Ethos research team, sought to determine the discriminant validity by comparing FPI scores of chronic pain subjects to age- and sex-matched pain-free controls. A total of 153 chronic pain patients and 334 sex-matched, pain-free controls urine samples were measured for levels of 11 urinary pain biomarkers and tabulated using a proprietary algorithm. FPI scores were compared to the 36-Item Short Form Health Survey (SF-36) scores among chronic pain subjects. The authors report FPI scores were significantly correlated with the 36-Item Short Form Health Survey (SF-36) scores among chronic pain subjects (P value < 0.015) and specific components of SF-36, including emotional well-being, limitations due to emotional problems, and general health (P value < 0.05). Area under ROC analysis (AUROC) revealed FPI to accurately distinguish biomarker profiles between pain-free and chronic pain cohorts (AUROC: 0.7490, P value < 0.0001) as well as the SF-36 scores between chronic pain subjects with low vs. high FPI scores (AUROC: 0.7715, P value < 0.01).⁸ Authors concluded these study findings establish the validity and discriminatory power of a novel multi-biomarker test that evaluates the role of biochemistry in chronic pain and correlates with clinical assessments. They go further to state the test provides reproducible, objective data which may pave the way for non-opioid therapeutic strategies to treat chronic pain. Biomarkers and FPI scores were assessed by a single point, cross-sectional analysis, and longitudinal monitoring through repeat FPI testing is necessary to establish the efficacy of modulating therapies. Limitations include observational design, risk of bias, lack of validation of the individual biomarkers used in the analysis and their role in pain management and confounding due to medication use and/or underlying medical conditions that were not evaluated. The authors also conclude these tools will likely improve compliance and motivate patients to adhere to the metabolic correction protocol, but this conclusion is beyond the scope the study and no data to support this conclusion was investigated.⁸

A 2020 randomized controlled trial (RCT) was conducted to examine the clinical utility of urine-based pain biomarker panel. Primary care physicians were randomized into the test group and compared to controls. Participants were randomly assigned to either intervention or control group in a 1:1 ratio using a coin flip methodology. Their ability to make the diagnosis and treat a total of nine standardized patients was measured, with common cases of chronic pain, over two rounds of data collection in a pre–post design. Intervention doctors received educational materials on a novel pain biomarker panel after the baseline round and had access to biomarker test results. The provider responses were measured against an evidence-based criteria developed by the investigators. They report that at baseline providers provided “similar poor care for three different primary pain pathways: (1.2% control versus 0% intervention treated, p = 0.152)”. They report that after receiving the results of the Foundation Pain Index (FPI) biomarker test, physicians in the intervention group were “41.5% more likely to make the diagnosis of a micronutrient deficiency, 29.4% more likely to identify a treatable metabolic abnormality and 26.1% more likely to identify an oxidative stressor”. The authors report diagnostic and treatment improvements ranging from a relative +54% (p = 0.004) for chronic neuropathic pain to +35% (p = 0.007) in chronic pain from other causes to +38% (p = 0.002) in chronic pain with associated mental health issues. They state that the intervention doctors were more likely (75.1%) to provide a non-opioid treatment to patients on chronic opioids (O.R. 1.8, 95% C.I. 0.8–3.7), 62% less likely to order unnecessary imaging for their patients with low back pain (O.R. 0.38, 95% C.I. 0.15–0.97) and 66% less likely to order an unnecessary pain referral (O.R. 0.34, 95% C.I. 0.13–0.90). The standard of practice that was used to establish this change was Measurement Using Clinical Performance and Value (CPV®) vignettes. The paper acknowledges the limitations include “practice impact opportunities for the provider and patient satisfaction was not considered, only considered three pain pathways, and multidisciplinary non-pharmacologic therapies for chronic pain, were not considered nor if they should be integrated with biomarker testing”. Authors concluded the study showed significant clinical utility of a validated pain biomarker panel that resulted in change of practice for chronic pain treatment.² Limitations of this study are the CPV® were designed to look for primary contributing diagnosis that are not established as cause of the primary diagnosis. For instance, lumbar spinal stenosis is caused by narrowing of the spinal foramen and the CPV states it is caused by Vitamin B12 deficiency and low serotonin syndrome which is not an established etiology of this pain condition. While this was the intent, as the authors postulate these alternative pathways may be associated with the underlying pain condition, it bypasses the standard of care for these conditions and lacks evidence to support a role for these pathways in management of the underlying conditions. It would not be expected the providers would identify and treat that condition based on the author’s criteria making the measurement for practice change invalid. The paper does not consider how chronic pain, underlying co-morbidities, mental health concerns may impact the test results and does not cite the source of the CPV and education used.²

Grading quality of evidence and strength using GRADE Pro software was conducted for the single RCT^9,10

^{Summary of findings:}

^{Urinary biomarker test for chronic pain compared to standard of care for impact treatment decisions by Primary Care Physicians (PCPs) for chronic pain patients} 

^{Patient or population: impact treatment decisions by Primary Care Physicians (PCPs) for chronic pain patients
Setting:
Intervention: urinary biomarker test for chronic pain
Comparison: standard of care} 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.

Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Explanations

a. Lack of blinding, randomization, COI.
b. Lack of diagnostic criteria for chronic pain, no quantification of pain.

Societal Input

The following Societal Guidelines were reviewed and there was no mention of urinary biomarkers as part of management pathways for chronic pain. There were also no treatment pathways that include specific nutritional or dietary interventions are part of standard of care treatment for chronic pain.

1. Practice Guidelines for Chronic Pain Management developed by the American Society of Anesthesiologist¹¹
2. The American Academy of Pain Medicine guidelines includes an evidence based document for use of clinical laboratory testing for monitoring drug therapy and pain management patients¹² and consensus recommendations for urine drug monitoring in patients receiving opioids for chronic pain.¹³
3. NICE Guidelines: Chronic pain in over 16s: assessment of all chronic pain and management of chronic primary pain.¹⁴
4. Institute for Clinical Systems Improvement (ICSI) guidelines for assessment of chronic in adults. The guidelines state “there is no diagnostic test for chronic pain”.¹⁵

Researchers have sought to identify biomarkers to help aid identification and management of chronic pain pathways. However, these pathways are not well understood, and specific targets have not been clearly identified. While efforts to identify these pathways are under investigation to date there is no moderate or high-quality evidence to support a role of biomarkers in the management of chronic pain. The Foundation Pain Index (FPI) test developed by Ethos Laboratories includes analysis of 11 endogenous analytes to evaluate biomarkers of systemic inflammation, oxidative stress, neurotransmitter turnover, and micronutrient status from urine samples. There are three papers that have been published that are specific to this test.

The first is a retrospective paper in which the authors studied the 11 biomarkers in patients with chronic pain and those without pain.⁷ They conclude that the test can effectively identify those with chronic pain. They feel that this can play a role in chronic pain management. However, this study has significant limitations including retrospective design, high risk of bias and multiple confounding aspects questioning the reliability of these findings.

The second paper was designed to assess clinical validity of the test. This is a cross-sectional observational study which sought to determine the discriminant validity by comparing FPI scores of chronic pain subjects to age- and sex-matched pain-free controls.⁸ The authors conclude the test is clinically valid and provides discriminatory power for their novel biomarker test. However, the individual biomarkers used in the test have not been validated for a role in pain management. Additionally, the initial study for which this test is based on low-quality evidence making the results of this study equally questionable. The study is also limited by observational design, risk of bias and confounding that has not been addressed in the study protocol.

The third study was designed to assess clinical utility of the FPI test. To establish clinical utility the test must be shown to play a role in the management of patients in clinical practice. In this randomized controlled trial (RCT) primary care physicians were assigned to an intervention group which received educational materials on novel pain biomarkers and received the biomarker results while the control group did not. The comparison was based on their ability to make the diagnosis and treat a total of nine standardized patients in a pre–post design. The authors reported a statistically significant difference in the ability of the intervention group to detect and treat micronutrient deficiency, metabolic abnormality, and oxidative stressor. They also state this reduced opioid prescriptions, imaging and referrals establishing clinical validity of the test.² Despite these findings the study is methodologically flawed. The study is based on a treatment protocol which is investigational. The treatment recommendations which are outlined within the tables of the study and include nutritional and supplemental management for the various pain scenarios is absent from societal guidelines and/or treatment pathways for these pain conditions and is not supported by robust evidence of any kind. In addition, the study is challenged by lack of blinding, randomization being made by a flip of a coin which is a risk for bias, and other risk of bias which lower the quality of the evidence to very-low quality on GRADE analysis (see above). The paper does not explain how chronic pain, underlying co-morbidities, mental health concerns contribute to the results nor cites the source of the CPV and education used. The paper does not provide insight if these management changes improved outcomes for patients or long-term follow-up.

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.

1. Borsook D, Becerra L, Hargreaves R. Biomarkers for chronic pain and analgesia. Part 1: the need, reality, challenges, and solutions. Discovery medicine. 2011;11(58):197-207.
2. Peabody J, Paculdo D, Tamondong-Lachica D, Cabaluna IT, Gunn J. Randomized Trial on the Clinical Utility of a Novel Biomarker Panel to Identify Treatable Determinants of Chronic Pain. Diagnostics (Basel). 2020;10(8).
3. Hagedorn JM, Gunn J, Budwany R, D’Souza RS, Chakravarthy K, Deer TR. How Well Do Current Laboratory Biomarkers Inform Clinical Decision-Making in Chronic Pain Management? Journal of Pain Research. 2021:3695-3710.
4. Aroke EN, Powell-Roach KL. The Metabolomics of Chronic Pain Conditions: A Systematic Review. Biol Res Nurs. 2020;22(4):458-471.
5. McDonagh MS, Selph SS, Buckley DI, et al. Nonopioid pharmacologic treatments for chronic pain. 2020.
6. David Tauben BRS. Approach to the management of chronic non-cancer pain in adults. https://www.uptodate.com/. Published 2023. Accessed 5/12/2023.
7. Gunn J, Hill MM, Cotten BM, Deer TR. An Analysis of Biomarkers in Patients with Chronic Pain. Pain Physician. 2020;23(1):E41-E49.
8. 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.
9. GRADEpro GDT: GRADEpro Guideline Development [Software]. McMaster University and Evidence Prime, 2022. Available from gradepro.org. Accessed May 12, 2023.
10. Schünemann H BJ, Guyatt G, Oxman A, editors. The GRADE Working Group. GRADE handbook for grading quality of evidence and strength of recommendations. Available from guidelinedevelopment.org/handbook. Published 2013. Accessed 5/12/2023.
11. Practice Guidelines for Chronic Pain Management: An Updated Report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine*. Anesthesiology. 2010;112(4):810-833.
12. Jannetto PJ, Langman LJ. Using clinical laboratory tests to monitor drug therapy in pain management patients. The Journal of Applied Laboratory Medicine. 2018;2(4):471-472.
13. Argoff CE, Alford DP, Fudin J, et al. Rational Urine Drug Monitoring in Patients Receiving Opioids for Chronic Pain: Consensus Recommendations. Pain Medicine. 2017;19(1):97-117.
14. Carville S, Constanti M, Kosky N, Stannard C, Wilkinson C, Guideline C. Chronic pain (primary and secondary) in over 16s: summary of NICE guidance. BMJ. 2021;373:n895.
15. Lambert M. ICSI releases guideline on chronic pain assessment and management. American family physician. 2010;82(4):434.

• Provider Education/Guidance