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] This test is a laboratory-developed test and therefore not regulated by FDA.(ECRI)

Literature search from PubMed, Google Scholar, Google, ClinicalTrials.gov, EBSCO Host with search words “chronic pain, pain biomarker OR oxidative stress” included 196 articles. An additional search was conducted on each biomarker included in the FPI panel. Three systematic reviews, 9 RCTs and 186 other papers and 11 citations added manually due to abstraction from bibliography were reviewed. The majority consisted 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 trials 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 out of 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 were 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]

The following peer reviewed original research on biomarkers submitted during the comment period was reviewed^[5-9] and review papers at^{[5 10-13]} were reviewed but added to evidence review.

A prospective cohort study investigated serum tryptophan metabolite levels, metabolite-ratios and metabolism pathway activation in patients with erosive and non-erosive hand osteoarthritis (HOA). The conclude tryptophan metabolites disturbance is associated with erosive HOA and pain and emphasize the role of low-grade inflammation and gut dysbiosis in HOA. While this study did show variations in these levels there was no comparison to patients without HOA or other types of pain. The authors postulate significant alterations in metabolites indicate potential involvement of gut dysbiosis and intestinal permeability in HOA patients, but this was not measured directly by stool sample. The authors conclude this provides a “new hypothesis for the hand osteoarthritis pathophysiology and potential new biomarkers”.^[14] Limitations of this study included cross-sectional design, lack of a non-HOA group, lack of stool sample utilization, exclusion of complementary measures of intestinal biomarkers, confounding as a result of intake of patients with previously gut microbiome alterations, and lack of measures of different pain types.

A prospective cohort study evaluating blood plasma analyzed for the following metabolites involved in the kynurenine pathway: tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykykynurenine (HK), anthranilic acid, xanthurenic acid (XA), 3-hydroxyanthranilic acid, quinolinic acid (QA) and picolinic acid in female patients aged 18 to 60 with chronic fatigue syndrome, fibromyalgia, and healthy controls. They conclude there is an association between kynurenine metabolism and chronic fatigue syndrome and fibromyalgia as well as characteristic symptoms like fatigue and pain.^[6] The study 's strengths included a control group and control for age, BMI and symptoms of anxiety and depression however it was not a randomized controlled trial introducing the potential risk of selection bias. Limitations include cross sectional design and causality cannot be established, self-report bias, and lack of dietary restricts for blood samples. The study was limited to female patients out of the Medicare age range, and inclusion of university and hospital staff for control group so not representative of general population.

A cross-sectional retrospective study on the correlation between pain frequency and severity and vitamin B12 levels in episodic and chronic migraine. 127 patients who were diagnosed as having migraine according to the International Classification of Headache Disorders (ICHDIII) were enrolled and 45 healthy controls. VAS scores were used to evaluate pain. Serum Vitamin B12 levels were obtained and considered low if below 300 ng/L.” Vitamin B12 levels were found to be significantly lower in migraineurs compared to the control group (227.30 ± 104.72 ng/L vs 278.44 ± 149.83 ng/L; p = 0.047). Chronic migraine (CM) patients had lower levels of vitamin B12 compared to patients with less frequent migraines (197.50 ± 69.16 ng/L vs 278.56 ± 147.91 ng/L; p = 0.019). Ratios of vitamin B12 levels of 300 ng/L and above in patients with CM was lower than that of patients with episodic migraine (p < 0.05).” Authors concluded the chronic migraine patients had lower vitamin B12 levels and a more holistic approach to care may be warranted. They note the need for more robust studies to support their findings.^[7] This study was limited by study design, moderate sample size, and a lack of measurement of folic acid, homocysteine and methylmalonic acid levels.

A cross-sectional study was conducted on 43 consecutive patients with Parkinson’s disease and 15 patients with peripheral neuropathy. Serum vitamin B12, methylmalonic acid (MMA), and homocysteine levels were obtained, and they found no correlation in the patients with peripheral neuropathy. MMA levels showed a positive correlation to neuropathy pain scales in the Parkinson’s disease patients with peripheral neuropathy, while Vitamin B12 and homocysteine showed no statistically significant correlation. They conclude serum MMA is a more sensitive marker than vitamin B12 in reflecting the severity of neuropathic pain in patients with IPD.^[8] Limitations include cross-sectional study design so causality cannot be established, and small sample size in Asian population so lacks generalizability.

Serum samples from 21 patients with definite clinical diagnosis of type 1 diabetes mellitus with neuropathic pain and was measured for 14 cytokines. They reported increases in two inflammatory biomarkers: neopterin and the kynurenine (KYN) and tetrahydrobiopterin (BH4) ratio, a marker of indoleamine 2,3-dioxygenase activity. They conclude the results suggest that inflammatory activation through elevated pro inflammatory cytokines neopterin and upregulation of the kynurenine pathway might be associated with neuropathic pain in type 1 diabetes mellitus and encourage future studies.^[9] Study is limited by study design and small sample size.

Lifestyle Modification and Nutritional and Supplemental Treatments for Pain and Inflammation

The basis of the FPI test is mechanistic insight into the underlying biochemical and nociceptive sources of pain so providers can design treatment approaches that target these pathologies at their core such as 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, dietary supplements and other modalities have been explored but the mechanism of these pathways are not clear, and interventions are 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, this demonstrates they are not considered as part of the standard management for chronic pain conditions at this time.^[15]

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^[16].

A systematic review and meta-analysis explore the impact of nutritional interventions on participants reported pain severity and intensity in a population with chronic pain.^[17] They included studies that explored overall diet (such as vegan, vegetarian, reduced fat diet), altered specific nutrition, supplementation and fasting. The meta-analysis concludes that nutritional interventions had a significant effect on pain reduction with the studies tested reporting an altered overall diet or just one nutrient having the greatest effect. In the supplementation analysis 11 studies reported statistically significant differences between groups in pain while the remaining 22 did not. The overall results were mixed and there was a lack of clear pattern of nutritional intervention to explain results. The meta-analysis included all types of nutritional interventions and the high heterogeneity between the included studies make the results unreliable. The authors conclude “The included studies are of limited quality and explore a range of nutrition interventions in those with chronic pain. This highlights the need for more rigorous nutrition intervention studies where chronic pain is the primary outcome. High-quality studies testing nutrition advice and support in populations with chronic pain and where pain is the primary outcome would be of benefit to researchers and clinicians.”

The evidence based recommendations for dietary ingredients as alternative approach for mitigation of pain^[18] conducted a systematic review and meta-analysis using GRADE. Nineteen eligible dietary ingredients were assessed for quality, efficacy, and safety. The panel concludes “Currently the scientific evidence is insufficiently robust to establish definitive clinical practice guidelines, but processes could be established to track the impact of these ingredients. Until then, providers have the evidence needed to make informed decisions about the safe use of these dietary ingredients, and future research can address existing gaps.”

Literature investigating the role of nutritional and dietary supplements for the management of a variety of underlying conditions including pain were reviewed.^[19-30] Additional investigation is needed to understand the role of these complementary and alternative therapies on the long-term outcome of the disease course or pain which is under investigation. Several studies demonstrate improvement in pain when Vitamin B12 deficiencies are present.^[31-35]

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. 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.^[36] 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 15]}

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. 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).^[29] 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.^[29]

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]

A 2021 retrospective observational study was conducted at a single center site to validate the Foundation Pain Index (FPI) by evaluating associations between deranged and biochemical function and PROMIS-29 domains.^[37] The study included 298 patients with chronic pain (defined as symptoms persisting longer than 3 months). Relationships between deranged biochemical function and quality of life outcomes were evaluated. Patients provided a urine sample and completed a PROMIS-29 survey 15 days of the initial encounter for pain biomarker testing. FPI domains including physical function, impact score, fatigue, pain interference, and depression were significantly associated with PROMIS-29 domains (P < 0.05). FPI analytes significantly correlated with PROMIS-29 domains (P <0.05). These included 5-hydroxyindolacetic acid (pain interference, physical function, and pain impact scores), hydroxymethylglutarate (physical function), homocysteine (pain impact scores), kynurenic acid (pain interference and physical function), and quinolinic acid (physical function). Authors conclude there is a strong association between FPI scores and clinical assessments in chronic pain patients. Limitations to this study include the retrospective observational design and reporting bias, and risk of bias associated with the study being conducted by Ethos.

Grading quality of evidence and strength using GRADE Pro software was conducted for the single RCT^{[38 39]}

^{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 Anesthesiologist^[40]
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 patients^[41] and consensus recommendations for urine drug monitoring in patients receiving opioids for chronic pain^[42].
3. NICE Guidelines: Chronic pain in over 16s: assessment of all chronic pain and management of chronic primary pain^[43].
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”.^[44]
5. PEER simplified chronic pain guideline: Management of chronic low back, osteoarthritic, and neuropathic pain in primary care^[45]
6. Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline from the American College of Physicians (2017)^[46]
7. The HHS pain management best practice Inter-Agency Task force report calls for patient-centered and individualized care^[47]

Genetic Test Assessment

A Genetic Test Assessment was conducted by ECRI concluding the evidence is inconclusive based on too little data on outcomes of interest.^[48] This report utilized clinical literature from January 1st 2018 to May 18th 2023 which included a full text case control study^[29] and a cohort study.^[37] The report expresses concerns about the very low quality evidence and reporting on too few patients to establish clinical validity of the FPI test. The report names the following limitation: the studies pooled patients included different chronic pain etiology limiting the ability to interpret results, and high risk of bias due to small sample size, single centered focus and retrospective design. The report states that clinical validity outcomes have not established for this test and health outcomes of patients whose management was guided based on the FPI tests are needed to establish clinical utility. The single study that randomized physician to online patient stimulations^[2] was not included in the analysis because it did not report on outcomes of interest.

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. Multiple papers on potential biomarkers were submitted during the Open Comment. These where all cross-sectional studies so cannot establish causality meaning the study is not sufficient to determine if the results of the biomarker are clearly linked to pathological condition being investigated. Additionally, these studies all measured biomarkers through blood serum and there is no evidence of correlation with urinary biomarker results. The current literature as it is unclear if the aberrant biomarker is from the underlying condition or related to chronic pain pathways. Also, during the open comment period multiple publications were submitted that explore the role of nutritional and supplementary treatment for the management of a variety of chronic conditions including pain. There is a lack of data to compare this approach to conventional management of these conditions. The long-term outcomes of these approaches are not established. In many cases they may offer an alternative or adjunctive treatments, but it is not clearly established at this time.

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 four 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.^[36] 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.^[29] 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 paper is a cross validation study.^[37] This retrospective observational study reports of statistically significant correlation between overall FPI scores and four of the measured PROMIS-29 domains, while there was no correlation with the other PROMIS-29 domains. The study is low-quality due to retrospective design. These two studies pooled patients with different chronic pain etiologies as well as use different instruments to evaluate and validate the test ability to identify and stratify patients with chronic pain and therefore do not validate each other 's findings.^[48]

The fourth study was designed to assess clinical utility of the FPI test.^[2] 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 48]} Despite these findings the study is methodologically flawed. The study is based 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 potential 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 compare outcomes for patients who received the test to those who did not receive the test and if the patient outcomes were changed by the test result. To establish clinical utility the test must influence not only the management of the patient based on the rest result, which this study does demonstrate, but the patient outcomes over time as a result is not addressed.

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) doi: 10.3390/diagnostics10080513[published Online First: Epub Date]|.
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 2021:3695-710
4. Aroke EN, Powell-Roach KL. The Metabolomics of Chronic Pain Conditions: A Systematic Review. Biol Res Nurs 2020;22(4):458-71 doi: 10.1177/1099800420941105[published Online First: Epub Date]|.
5. Jovanovic F, Candido KD, Knezevic NN. The Role of the Kynurenine Signaling Pathway in Different Chronic Pain Conditions and Potential Use of Therapeutic Agents. Int J Mol Sci 2020;21(17) doi: 10.3390/ijms21176045[published Online First: Epub Date]|.
6. Groven N, Reitan SK, Fors EA, Guzey IC. Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome, Fibromyalgia, and healthy controls. Psychoneuroendocrinology 2021;131:105287 doi: 10.1016/j.psyneuen.2021.105287[published Online First: Epub Date]|.
7. Üstün Özek S. A study on the correlation between pain frequency and severity and vitamin B12 levels in episodic and chronic migraine. Arquivos de Neuro-Psiquiatria 2022;80:586-92
8. Park JS, Park D, Ko PW, Kang K, Lee HW. Serum methylmalonic acid correlates with neuropathic pain in idiopathic Parkinson's disease. Neurol Sci 2017;38(10):1799-804 doi: 10.1007/s10072-017-3056-9[published Online First: Epub Date]|.
9. Staats Pires A, Heng B, Tan VX, et al. Kynurenine, Tetrahydrobiopterin, and Cytokine Inflammatory Biomarkers in Individuals Affected by Diabetic Neuropathic Pain. Front Neurosci 2020;14:890 doi: 10.3389/fnins.2020.00890[published Online First: Epub Date]|.
10. Athnaiel O, Ong C, Knezevic NN. The Role of Kynurenine and Its Metabolites in Comorbid Chronic Pain and Depression. Metabolites 2022;12(10) doi: 10.3390/metabo12100950[published Online First: Epub Date]|.
11. Tanaka M, Torok N, Toth F, Szabo A, Vecsei L. Co-Players in Chronic Pain: Neuroinflammation and the Tryptophan-Kynurenine Metabolic Pathway. Biomedicines 2021;9(8) doi: 10.3390/biomedicines9080897[published Online First: Epub Date]|.
12. Tracey I, Woolf CJ, Andrews NA. Composite pain biomarker signatures for objective assessment and effective treatment. Neuron 2019;101(5):783-800
13. Bäckryd E. Pain in the blood? Envisioning mechanism-based diagnoses and biomarkers in clinical pain medicine. Diagnostics 2015;5(1):84-95
14. Binvignat M, Emond P, Mifsud F, et al. Serum tryptophan metabolites are associated with erosive hand osteoarthritis and pain: results from the DIGICOD cohort. Osteoarthritis Cartilage 2023 doi: 10.1016/j.joca.2023.04.007[published Online First: Epub Date]|.
15. McDonagh MS, Selph SS, Buckley DI, et al. Nonopioid pharmacologic treatments for chronic pain. 2020
16. David Tauben BRS. Approach to the management of chronic non-cancer pain in adults. Secondary Approach to the management of chronic non-cancer pain in adults 2023. https://www.uptodate.com/.
17. Brain K, Burrows T, Rollo M, et al. A systematic review and meta-analysis of nutrition interventions for chronic noncancer pain. Journal of Human Nutrition and Dietetics 2019;32(2):198-225
18. Crawford C, Boyd C, Paat CF, et al. Dietary ingredients as an alternative approach for mitigating chronic musculoskeletal pain: evidence-based recommendations for practice and research in the military. Pain Medicine 2019;20(6):1236-47
19. Chiu C, Low T, Tey Y, Singh VA, Shong H. The efficacy and safety of intramuscular injections of methylcobalamin in patients with chronic nonspecific low back pain: a randomised controlled trial. Singapore medical journal 2011;52(12):868-73
20. Battisti E, Albanese A, Guerra L, Argnani L, Giordano N. Alpha lipoic acid and superoxide dismutase in the treatment of chronic low back pain. Eur J Phys Rehabil Med 2013;49(5):659-64
21. Letizia Mauro G, Cataldo P, Barbera G, Sanfilippo A. α-Lipoic acid and superoxide dismutase in the management of chronic neck pain: a prospective randomized study. Drugs in R&D 2014;14:1-7
22. Geller M, Mibielli MA, Nunes CP, da Fonseca AdS, Goldberg SW, Oliveira L. Comparison of the action of diclofenac alone versus diclofenac plus B vitamins on mobility in patients with low back pain. Journal of drug assessment 2016;5(1):1-3
23. Ramakanth G, Kumar CU, Kishan P, Usharani P. A randomized, double blind placebo controlled study of efficacy and tolerability of Withaina somnifera extracts in knee joint pain. Journal of Ayurveda and integrative medicine 2016;7(3):151-57
24. Agathos E, Tentolouris A, Eleftheriadou I, et al. Effect of α-lipoic acid on symptoms and quality of life in patients with painful diabetic neuropathy. Journal of International Medical Research 2018;46(5):1779-90
25. Sergi G, Pizzato S, Piovesan F, Trevisan C, Veronese N, Manzato E. Effects of acetyl-L-carnitine in diabetic neuropathy and other geriatric disorders. Aging clinical and experimental research 2018;30:133-38
26. Derosa G, D'Angelo A, Maffioli P. Coenzyme q10 liquid supplementation in dyslipidemic subjects with statin-related clinical symptoms: a double-blind, randomized, placebo-controlled study. Drug Des Devel Ther 2019;13:3647-55 doi: 10.2147/DDDT.S223153[published Online First: Epub Date]|.
27. Hamilton DE, Jensen GS. Pain reduction and improved vascular health associated with daily consumption of an anti-inflammatory dietary supplement blend. Journal of Pain Research 2019:1497-508
28. Nachvak SM, Alipour B, Mahdavi AM, et al. Effects of coenzyme Q10 supplementation on matrix metalloproteinases and DAS-28 in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled clinical trial. Clinical Rheumatology 2019;38:3367-74
29. 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):511-29 doi: 10.1007/s40122-020-00175-3[published Online First: Epub Date]|.
30. Cross W, Srivastava S. A Double-Blind, Randomized, Placebo-Controlled Study to Assess the Efficacy of a Nerve Support Formula on Neuropathic Pain in Individuals Suffering from Type II Diabetes Mellitus. Journal of Pain Research 2023:1115-26
31. Wang J, Wu Y, Liu S, Lin Y, Lu P. Vitamin B12 for herpetic neuralgia: A meta-analysis of randomised controlled trials. Complementary therapies in medicine 2018;41:277-82
32. Karedath J, Batool S, Arshad A, et al. The impact of vitamin B12 supplementation on clinical outcomes in patients with diabetic neuropathy: A meta-analysis of randomized controlled trials. Cureus 2022;14(11)
33. Casey M-B, Smart KM, Segurado R, Doody C. Multidisciplinary-based Rehabilitation (MBR) compared with active physical interventions for pain and disability in adults with chronic pain: a systematic review and meta-analysis. The Clinical Journal of Pain 2020;36(11):874-86
34. Buesing S, Costa M, Schilling JM, Moeller-Bertram T. Vitamin B12 as a treatment for pain. Pain physician 2019;22(1):E45
35. Julian T, Syeed R, Glascow N, Angelopoulou E, Zis P. B12 as a treatment for peripheral neuropathic pain: a systematic review. Nutrients 2020;12(8):2221
36. Gunn J, Hill MM, Cotten BM, Deer TR. An Analysis of Biomarkers in Patients with Chronic Pain. Pain Physician 2020;23(1):E41-E49
37. Pope JE FM, Gunn JA, Cotten BM, Hill MM, Deer TR. . Cross Validation of Foundation Pain Index with PROMIS-29 in Chronic Pain Patients

J Pain Res 2021;14(August 29):62677-2685 doi: 10.2147/JPR.S314021[published Online First: Epub Date]|.

38. [Software]. GGGGDT. Secondary 2022. gradepro.org.
39. Schünemann H BJ, Guyatt G, Oxman A, editors. The GRADE Working Group, . GRADE handbook for grading quality of evidence and strength of recommendations. . Secondary GRADE handbook for grading quality of evidence and strength of recommendations. 2013. Available from guidelinedevelopment.org/handbook.
40. 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):810-33 doi: 10.1097/ALN.0b013e3181c43103[published Online First: Epub Date]|.
41. 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):471-72
42. 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 doi: 10.1093/pm/pnx285[published Online First: Epub Date]|.
43. 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 doi: 10.1136/bmj.n895[published Online First: Epub Date]|.
44. Lambert M. ICSI releases guideline on chronic pain assessment and management. American family physician 2010;82(4):434
45. Korownyk CS, Montgomery L, Young J, et al. PEER simplified chronic pain guideline: Management of chronic low back, osteoarthritic, and neuropathic pain in primary care. Canadian Family Physician 2022;68(3):179-90
46. Qaseem A, Wilt TJ, McLean RM, Forciea MA, Physicians* CGCotACo. Noninvasive treatments for acute, subacute, and chronic low back pain: a clinical practice guideline from the American College of Physicians. Annals of internal medicine 2017;166(7):514-30
47. Cheng J, Rutherford M, Singh VM. The HHS pain management best practice Inter-Agency Task force report calls for patient-centered and individualized care: Oxford University Press, 2020:1-3.
48. ECRI. Genetic Test Assessment: Foundation Pain Index (Ethos Laboratories) for Guiding Management of Chronic Pain. Secondary Genetic Test Assessment: Foundation Pain Index (Ethos Laboratories) for Guiding Management of Chronic Pain June 2023. https://www.ecri.org/.
49. Auyeung A, Wang HC, Aravagiri K, Knezevic NN. Kynurenine Pathway Metabolites as Potential Biomarkers in Chronic Pain. Pharmaceuticals (Basel) 2023;16(5) doi: 10.3390/ph16050681[published Online First: Epub Date]|.
50. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. Jama 2016;315(15):1624-45
51. Freo U, Brugnatelli V, Turco F, Zanette G. Analgesic and Antidepressant Effects of the Clinical Glutamate Modulators Acetyl-L-Carnitine and Ketamine. Front Neurosci 2021;15:584649 doi: 10.3389/fnins.2021.584649[published Online First: Epub Date]|.
52. Haleem DJ. Targeting Serotonin1A receptors for treating chronic pain and depression. Current neuropharmacology 2019;17(12):1098-108
53. Christofides EA, Valentine V. L-Methylfolate in Diabetic Peripheral Neuropathy: A Narrative Review. Endocr Pract 2023 doi: 10.1016/j.eprac.2023.04.005[published Online First: Epub Date]|.
54. Katz G, Ogdie A, Baker JF, George MD. Association between depression, anxiety, chronic pain, or opioid use and tumor necrosis factor inhibitor persistence in inflammatory arthritis. Clin Rheumatol 2022;41(5):1323-31 doi: 10.1007/s10067-021-06045-3[published Online First: Epub Date]|.
55. Langan RC, Goodbred AJ. Vitamin B12 deficiency: recognition and management. American family physician 2017;96(6):384-89
56. Mead P, Petersen J, Hinckley A. Updated CDC recommendation for serologic diagnosis of Lyme disease. Morbidity and Mortality Weekly Report 2019;68(32):703-03
57. Miranda-Massari JR, Gonzalez MJ, Jimenez FJ, Allende-Vigo MZ, Duconge J. Metabolic correction in the management of diabetic peripheral neuropathy: improving clinical results beyond symptom control. Curr Clin Pharmacol 2011;6(4):260-73 doi: 10.2174/157488411798375967[published Online First: Epub Date]|.
58. Moccia M, Capacchione A, Lanzillo R, et al. Coenzyme Q10 supplementation reduces peripheral oxidative stress and inflammation in interferon-beta1a-treated multiple sclerosis. Ther Adv Neurol Disord 2019;12:1756286418819074 doi: 10.1177/1756286418819074[published Online First: Epub Date]|.
59. Nguyen N, Takemoto JK. A Case for Alpha-Lipoic Acid as an Alternative Treatment for Diabetic Polyneuropathy. J Pharm Pharm Sci 2018;21(1s):177s-91s doi: 10.18433/jpps30100[published Online First: Epub Date]|.
60. Pangarkar SS, Kang DG, Sandbrink F, et al. VA/DoD clinical practice guideline: diagnosis and treatment of low back pain. Journal of general internal medicine 2019;34:2620-29
61. Poncelet AN. An algorithm for the evaluation of peripheral neuropathy. American family physician 1998;57(4):755-64
62. Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes care 2017;40(1):136
63. Salehi B, Berkay Yilmaz Y, Antika G, et al. Insights on the use of α-lipoic acid for therapeutic purposes. Biomolecules 2019;9(8):356
64. Sarzi-Puttini P, Giorgi V, Di Lascio S, Fornasari D. Acetyl-L-carnitine in chronic pain: A narrative review. Pharmacol Res 2021;173:105874 doi: 10.1016/j.phrs.2021.105874[published Online First: Epub Date]|.
65. Silberstein S, Holland S, Freitag F, Dodick D, Argoff C, Ashman E. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78(17):1337-45

The following papers were reviewed but not cited in the LCD^[49-65]