Response to Comments: Urinary Biomarkers for Chronic Pain Management

Comments were received from Pacific Rehabilitation and Pain in Monterey CA. The commenter states that they disagree with the non-coverage position of the LCD stating:

1. Foundation Pain Index has been clinically validated in two prospective, peer-reviewed studies and shown to correlate with Quality-of-life (QoL) measures as scored by the SF-36 and the PROMIS-29.
2. Worsening biochemical function, as measured by FPI, correlated strongly with pain, fatigue, depression, and physical functioning domains further confirming the role of perturbed biochemical function in chronic pain.
3. Foundation Pain Index demonstrated significant clinical utility in a prospective, randomized controlled trial. Specifically, FPI was shown to improve diagnostic accuracy, reduce unnecessary imaging for low back pain, and reduce opioid prescribing.

4. FPI provides novel objective insight into the neurobiological underpinnings of chronic pain which provides practitioners with opportunities for targeted interventions to alleviate pain and improve quality of life.

Supporting literature was not submitted with these comments.

Thank you for your comments. The two prospective peer-reviewed studies mentioned and reviewed in the evidence section of the LCD were conducted to establish clinical validity for the FPI test have notable limitations as outlined in the LCD. Most concerning was the study design, considerable risk of bias, and pooled patients of different chronic pain etiologies limiting the ability to interpret the result. This results in very low-quality evidence. The RCT, also discussed in the LCD, was also very low quality due, randomization, diagnostic criteria for chronic pain, standards for quantification of pain and risk of bias. Additionally, the study lacked outcome data which is essential to understand if the test improves outcomes for those whose management was modified by the test results. Therefore, CGS Administrators do not find sufficient evidence to support coverage of the FPI test based on current literature and consider the test investigational.

A pain management provider from Jamestown, CA commented:

They explain that pain is subjective, and it is difficult to have an objective measurement. They share that using Functional Pain Index obtained through urine biomarkers gives them something to review with patients and offers them the ability to be part of their healthcare decision making and efforts in our practice have been shown to reduce overall morphine milliequivalents of some patients as they follow recommendations. They share support of coverage for the test.

Supporting literature was not submitted with these comments.

Thank you for your comments and we agree with the importance of recognizing and treating pain, continued efforts to develop better tools to aid in pain measurements and management and efforts to reduce opioid use. Nonetheless, there is not sufficient evidence to support the currently available urinary biomarker for chronic pain test. There is no published literature that this test improves health outcomes for beneficiaries or reduces opiate use. Additional investigation is needed for this test to meet the requirements of reasonable and necessary required for Medicare coverage.

Multiple providers, the California Society of Interventional Pain Physicians and multiple pain management practices from across the country submitted letters of support for the Foundational Pain Index test stating that it aids them in making informed treatment decisions and benefits their patients.

There was no new peer reviewed published literature submitted with these comments.

Thank you for your comments. See Comments 1 & 2.

Three review papers^[1-3] were referenced with supporting comments for urinary biomarkers. These manuscripts review the role of Kynurenine as a potential biomarker for chronic pain.

These studies review the potential role of kynurenine as a biomarker for pain and postulate a mechanism for this function. One is a concept paper for animal models for future investigations.^[3] Another is a review^[1] (not systematic) about current literature on kynurenine in depression and chronic pain calling for further investigations on this potential role as a biomarker. The third reviews (not systematic) the potential for kynurenine pathway and metabolites to function as a biomarker for chronic pain and calls for further studies to clarify this role.^[2]

We appreciate the submission of this literature and look forward to future investigation to further understand this potential biomarker for chronic pain.

Several providers wrote similar letters to endorse the FPI test for chronic pain management and stated concern with the statement “the role of the individual biomarkers in chronic pain is not clearly established” and disagrees stating there is peer-reviewed literature on this subject and the test has been validated. Additionally, they stated the key word search was too narrow and the test has been validated.

Supporting literature was not submitted with these comments.

Thank you for your comments. See Comments 1 & 2. As stated in the LCD a total of 196 manuscripts were included in the initial literature review and each of the biomarkers included in the FPI test were included in the search. While these papers were not included in the proposed draft evidence analysis due to lack of high-quality evidence on the individual biomarkers this has been added to final version. Despite this robust search, there is not a clear role for biomarkers in chronic pain management. Additional research may establish further understanding of the complex mechanism of pain and the role of biomarkers, but at this point it remains investigational.

The American society of Pain and Neuroscience submitted comments stating that the initial literature search was too narrow, and the societal guidelines referenced in the LCD would not necessarily include diagnostic test such as urinary biomarkers in their algorithms. The state “A validated biomarker assay provides objective support and quantifying the neurobiological processes contributing to chronic pain. Some functional pain biomarkers like FPI (Foundation Pain Index) provides practitioners with normal, objective insight into the underlying cause of pain which will pave the way for truly personalized pain medicine. The clinical and analytical validity of some biomarker assays have been clearly established through rigorous cross-sectional designed studies.” The go on to state the critical need to develop innovations for non-opiate pain management and the associated reduced cost if that is achieved. And request coverage for the test.

Thank you for your comments and submitted references. See Comment #5.

Six papers were referenced in the submitted comments. Of these 4 were included in the LCD (References 2, 3, 7 and 8). The LCD provides the analysis of this literature, and these papers are further elaborated in Response #1 & 2 above. The additional 2 references, “The underestimated cost of the opioid crisis” and “Prescription opioid abuse: a literature review of the clinical and economic burden in the United States” are specific to the opiate crisis and cost. These are not added to the LCD since cost is not considered for Medicare coverage decisions and as discussed in Comment #2 above there is no published literature that this test improves health outcomes for beneficiaries or reduces opiate use. Therefore, CGS disagrees with the statement the literature search was too narrow as addressed in Response #5. If new peer reviewed papers pertinent to this subject are published it can be submitted through the LCD reconsideration process.

Eleven comments were received from Clinical and Life Science Program:

Comment 1 & 2- The commenter disagrees with several sentences in the LCD that were directly quoted from the referenced research paper.

Comment 3- Regarding "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.” The comment states “We would like to clarify that the criteria used to determine the diagnostic and treatment scores are based on evidence-based parameters and include standard of care. The diagnostic and treatment scores measure all interventions ordered by the physician, on top of prescribing standard of care, as recommended by applicable guidelines^[4-10]- the 8^th was not reviewed since it was retired.

Comment 4- The commenter disagrees with the LCD “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” stating we incorrectly conflates the primary diagnosis with a successful treatment intervention and that the study is on physician behavior.

Comment 5- This comment focuses on the challenges in treatment of chronic pain^{[11 12]} and states that patients identified by biomarkers had more non-opioid pain management and complementary management. The US HHS report^[11] was submitted to show a wide variation in diagnosis and management in chronic pain and lack of understanding of chronic pain pathways.

Comment 6- The commenter requests clarification of the statement “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 state the purpose of this study is to ask: If doctors are aware of these deficiencies, do they respond to the FPI results? They also state when nutritional deficiencies are found and treated pain is improved as demonstrated in a systematic review.^[13]

Comment 7- The commenter responds to statement in LCD "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” They state that underlying comorbidities and mental health concerns are associated with worse pain outcomes. They state the clinical vignettes created by the test developer based on guidelines and considered these factors in the vignettes.

Comment 8- the commenter objects to statement in LCD that "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" stating the vignettes address guideline based and complementary therapies. The commenter states “There is also huge heterogeneity in current studies in terms of outcome measures and interventions used^[14] research studies would have varying measures for assessing pain, response to therapy, dose of medication, and mode and frequency of intervention. This limits the availability of evidence that is of a scale significant enough to warrant inclusion in guidelines.”

Comment 9 - The comment states that “The relevance and applicability of blinding varies depending on circumstance” and a commentary was provided.

Comment 10- The comment argues with statement "In addition, the study is challenged by…randomization being made by a flip of a coin which is a risk for bias” stating there are various kinds of bias related to flip of coin and it is potential for bias but not that bias has occurred.

Comment 11- The commenter states that the statement in LCD "The paper^[15] does not provide insight if these management changes improved outcomes for patients or long-term follow-up.” The commenter clarifies the “The referenced paper looked specifically at whether intervention participants changed their practice based on the results of the FPI test in simulated patients” The results of the paper show that there is a clear and significant difference between intervention and control participants, indicating clinical utility to the physicians. The practice change identified compels use of FPI, as well as further patient-level studies to investigate impact. They state they saw a significant 62% reduction in imaging for patients with chronic low back pain and a 66% reduction in making low-value referrals to pain specialists. These improvements lower potential direct costs to the patient. Next, we looked at guidelines for chronic pain, and conservatively, nonpharmacologic treatments had small effects and little evidence of long-term effectiveness (3,4).”

Response 1 & 2- The quote that was included in this comment was directly quoted from the research paper referenced.

Response 3- None of 8 referenced Guidelines included biomarkers in their guidelines. Some guidelines included search for nutritional deficiencies (mostly Vitamin B deficiencies) in the differential diagnosis for diabetic neuropathy, but no mention of nutritional pathways for chronic pain management. None of the Guidelines recommend utilization of biomarkers for pain evaluation and management.

Response 4-We agree the study investigates physician behavior and why it does not establish clinical utility which requires a change in patient outcomes because of the test. In this study the providers may indicated a change in treatment pathways such as not ordering a consultation, not ordering unnecessary imaging or prescribing opiates however we do not know whether these changes impact patient care. This data obtained at a single visit and there is no longitudinal follow up to determine if the patient's pain improved because of the change in management. Additional these actions may have occurred at follow-up and therefore the behavior was only changes for a single visit. Therefore, we do not understand if patients’ pain, and outcomes are improved because of the change in management.

The LCD is stating that the pain pathways investigated in this paper compared standard of care scenarios with alternative treatment options. The providers would not be expected to correctly identify the protocols since they are not represented in standard of care practice as exemplified in the guidelines submitted in Comment 3. The concern is that the there is insufficient evidence to understand if the proposed alternative treatment pathways result in improved outcomes.

Response 5- We agree with the HHS Task Force paper that pain is best managed with a multimodal approach, and this has been supported in the literature.^[11] While the task force paper does call out complementary and integrative therapies as part of the armamentarium for pain treatment, they specially refer to acupuncture, massage, movement therapy and does not mention the treatment pathways currently in the FPI Guidelines. The task force paper does not mention use of biomarkers for pain management.^[11]

Response 6- CGS agrees that the Peabody paper demonstrates that given the results of FPI results providers may treat underlying deficiencies because of the test, but how that impacts patient outcomes is not established. In the systematic review provided^[13] the literature reviewed papers that investigated a variety of dietary alternations in patients with chronic pain and the outcomes. This included dietary changes from vegan or vegetarian diet, reducing fat intake, fasting to supplementation. 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. While a meta-analysis was conducted it included all types of nutritional interventions and the high heterogeneity between the included studies make the results unreliable. The authors conclude “However, 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.” There is not data to determine which treatments results in improvements or duration of change. The study is not high quality as the meta-analysis included all types of nutritional interventions and the high heterogeneity between the included studies make the results unreliable.

Response 7- The current FPI does not account for potential changes in the measured biomarkers being caused by underlying conditions which can impact these test results in patients with or without pain and is a limitation of the current test. The issue being it is unclear if the abnormal result is from pain or the underlying condition. Of the 5 papers submitted with this comment one reports on a link between depression and pain which demonstrates this point.^[16] This challenges the sensitivity of the test for pain detection. The referenced Practice Guidelines, NICE report, ACP Chronic Pain Clinical Practice Guidelines and PEER Guidelines do not mention biomarkers or nutrition in the reports.^[17-20] The absence of biomarkers from these guidelines demonstrates this has not been incorporated into standard of care practice.

Response 8- The heterogeneity in current studies^[14] is a limitation of current literature as there is a lack of standard practice. This must be established to meet the definition of reasonable and necessary which is defined as the service must be furnished in accordance with accepted standards of medical practice for diagnosis and treatment. This lack of standard is a key factor in why urinary biomarkers for chronic pain management is considered investigational. Of the 8 referenced papers 3 are review papers and not peer reviewed publications, 2 address the role of Vitamin B12 for pain^{[21 22]} for which we agree if there is a known deficiency it should be treated but does not require a lab panel for diagnosis. The evidence based recommendations for dietary ingredients as alternative approach for mitigation of pain^[23] 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.” which aligns with the concerns addressed in LCD regarding lack of evidence to support this.

Response 9- We agree you cannot blind an intervention where the study is designed to see if the provided information changes physician behavior and has been removed from LCD. While the study address if the provider would change management based on test results there is not data if those changes are effective and improve outcomes which is necessary to establish clinical utility.

Response 10- Potential bias has been added to LCD. There are multiple papers in the literature regarding the risk of bias associated with flip of a coin which has a higher potential of manipulation than other randomization techniques. In the literature submitted to support this comment the Kang et al paper states:“Although randomization may be accomplished with a simple coin toss, more appropriate and better methods are often needed, especially in small clinical trials.”^[24]

Response 11- See Response 7/Section 4 &6 above. We disagree that the Peabody^[15] paper establishes clinical utility. In this paper the primary outcome was the change in the diagnostic and treatment scores. We agree there was a change in the score as would be predicted if introducing a novel treatment pathway. The improvement reported is based on if the providers treatment plan changes but does not measure patient outcomes. 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 test result (which the Peabody paper does demonstrate) but the patient outcomes over time as a result is not addressed. This was consistent with recent ECRI Genetic Test Assessment conclusion.^[25]

Ten comments were received from the Ethos Research Team:

Comment 1- This comment expresses concern with the key search to include only chronic pain, pain biomarkers or oxidative stress utilized in the initial search review and concern that this omitted high quality publications and suggest inclusion of multiple additional ICD 10/11 codes. 9 references were included.

Comment 2- Submitted Pope et al^[26] publication and a summary of the study.

Comment 3- The comment explains why there are no FDA approved biomarkers for pain since pain is subjective. They also state while the subjective experience of pain cannot be measured there are objective measures for some of the various biochemical and pathological processes which drive chronic pain. They state FPI does not determine presence of absence of pain but detects underlying biochemical pathway aberrations therefore linked to chronic pain.

Comment 4- The commenter discusses the role of the FPI test is not to not based on specific interventions, such as nutrition based, but based on knowledge that pain can develop from multiple pathways. Nutrition approaches, especially those mentioned in the LCD, is only a pathway to correct an abnormality detected by FPI test and part of an overall evaluation.

Comment 5- The comment argues against comparing the FPI test to other non-pharmaceutical complementary medicine specifically acupuncture which is one of the examples in the LCD.

Comment 6- The commenter questions the relevancy of the AHRQ systematic review and meta-analysis under lifestyle modifications and nutritional treatment for pain section of the LCD because dietary supplementation was not included in the analysis. They have attached additional peer review literature that they request review for supporting the role of non-pharmacological agents in the management of pain related conditions.

Comment 7- The commenter references the section of the LCD which discusses dietary interventions and emphasizes that the basis for FPI is not simply to drive dietary changes but to provide objective, mechanistic insight into the underlying biochemical and nociceptive sources of pain so physicians can design treatment approaches that target these pathologies at their core. They state that their plan for treatment is to include targeted treatment directed towards the underlying pain source facilitated by FPI testing.

Comment 8- The commenter disagrees with the statement in the policy that “the role of individual biomarkers in chronic pain is not clearly established and there are not specific biomarkers for chronic pain”. They submitted additional peer review literature which they request be reviewed as they feel that the literature search was limited and therefore overlooked the evidence for these biomarkers. They state the basis for the Foundation Pain Index is “A validated, mechanistic biomarkers that allow for the objective evaluation of biochemical function in the context of chronic pain.”

Comment 9- In response to section in the LCD that states the FPI scores were assessed by single point, cross-sectional analysis they responded that a current clinical trial is ongoing to investigate the impact of biomarker guided therapy longitudinally.

Comment 10- In response to the concern in the LCD that addresses the lack of validation of the individual biomarkers used in the analysis as mentioned in the LCD the commenter states that “It should be noted that individual biomarkers of the FPI have been validated as robust surrogate markers of their respective biochemical pathways. Ethos Laboratories did not discover these biomarkers as novel markers but rather developed a comprehensive panel of markers based on evidence in the peer-reviewed literature.”

Thank you for the comments and submitted literature.

Response 1- Please see Comments #4 & 6. The references include a paper on serum tryptophan metabolites and erosive hand osteoarthritis^[27], a paper on kynurenine signaling in chronic pain, cluster headaches, chronic fatigue and fibromyalgia depression^[1] and diabetic neuropathic pain^{[3 28-31]}, a study on Vitamin B12 levels and migraine^[32], serum methylmalonic acid and neuropathic pain in Parkinson’s disease^[33]. The papers do not clearly link the metabolite with chronic pain, but some are promising. This represents the need for additional research to further understand the role of biomarkers and pain as stated in the papers. Several of the referenced papers evaluate serum measurements of biomarkers so correlation to urine testing is also needed.

Response 2- Pope et al has been added to the LCD with summary and evidence analysis. Thank you for submitting.

Response 3- Two papers were submitted with this comment. One is a concept paper calling for more translational pain research to better understand pain medicine including biomarkers.^[34] The second is a call for investigation of biomarkers.^[35] This aligns with our position that biomarkers for chronic pain is investigational.

Response 4- We agree with the state role of the FPI test, however, to establish clinical utility the results of the test must be actionable and result in a change of management with measurable patient outcomes. Nutritional pathways were included in the clinical vignettes to measure practice changes however outcomes have not yet been measured to establish clinical validity. See Response #7.

Response 5- The examples were removed from the LCD to avoid any confusion. Seven references were submitted with this comment which highlight potential biomarkers and role in various diseases or pain.^[36-42] These supports that biomarker’s role in chronic pain is investigational.

Response 6- The AHRQ report is relevant as it demonstrates that nutritional and other supplementations are not considered part of standard of care and therefore not included in guidelines or systematic reviews that access non-opioid treatment pathways. See Comment 7 (specifically Response 8) addresses standard of care for establishing reasonable and necessary for Medicare. The referenced literature^[43-54] investigates multiple supplements in a variety of conditions, however none of these are part of established standard of care and most papers call for additional research to further understand their roles. Additionally, many are seeking a role for biomarkers in specific medical conditions such as rheumatoid arthritis or diabetic neuropathy this exemplifies the challenge of understanding if the aberrant biomarkers are due to the underlying condition or related to pain pathways. If the biomarker is from an underlying condition management of that condition may be optimal to reduce pain and they may not benefit from treatment pathways linked to FPI. As far as the role of supplementation or replacements for treating the conditions there is a paucity of literature to support this role and lack of data to compare this approach to conventional management of these conditions. In many cases they may be adjunctive treatments, but it is not clearly established at this time. This is why clinical utility to understand the impact of the test on patient outcomes is critical. The role of Vitamin B is discussed in Comment 7/ Response 8.^{[55 56]}

Response 7- See Comment 7 above.

Response 8- Multiple papers on potential biomarkers were submitted and as requested reviewed and added to evidence section of the LCD. Review papers, which did not offer novel investigation, were reviewed but not added to evidence review. 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 that is utilized in the urinary biomarker pain index test. See Comment #5 & 6 above regarding literature search.

Response 9- New peer reviewed published literature can be submitted through the LCD reconsideration process.

Response 10- We do not agree that there is robust literature to support the individual biomarkers included in the panel. There is sufficient literature that there is a direct link between vitamin B12 levels and pain however this does not require a comprehensive panel to measure. Also, the correlation between the serum levels and urinary measurements is not established. Additional investigation is necessary to further delineate the role of biomarkers for chronic pain.

Combined supporting documentation received: 

1. 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]|.
2. 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]|.
3. 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]|.
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