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

****

**Background**

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

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

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

_Biomarkers for Chronic Pain_

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

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

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

_Lifestyle Modification and Nutritional Treatments for Pain_

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

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

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

_Foundational Pain Index (FPI)_

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

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

****

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

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

#### **Summary of findings:**

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

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

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

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

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

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

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

Currently there is not established evidence to support a role of urinary
biomarkers for management of chronic pain, therefore CGS Administrators
consider urinary biomarker test for chronic pain experimental and non-covered.