**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

Outcomes  |

**Anticipated absolute effects ***(95% CI)

**Risk with standard of care**

|

**  Anticipated absolute effects***(95% CI)

**Risk with urinary biomarker test for chronic pain**

| Relative effect  
(95% CI) | No of  
participants  
(studies)  | Certainty of  
the evidence  
(GRADE) | Comments  
---|---|---|---|---|---|---  
Change in treatment  
assessed with: CPV  
scores | 0 per 1,000 | 0 per 1,000  
(0 to 0) | not estimable | 151  
(1 RCT) |

Very low2,a,b

|  
  
***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.