How Well Do Current Laboratory Biomarkers Inform Clinical Decision-Making in Chronic Pain Management?

OBJECTIVE: Decision-making in chronic pain patients involves a combination of subjective and objective criteria, including patient history, physical examination, imaging, and patient response to prior treatments, clinical experience, probabilities, and recognition of patterns. However, there is a distinct lack of objective laboratory biomarkers in use in routine clinical care. The objective was to review the literature to identify and describe specific biomarkers in chronic pain management. METHODS: This is a narrative review of the literature regarding the use of laboratory biomarkers in chronic pain. A librarian-assisted literature search of the PubMed, Science Direct, and Google Scholar databases was performed and resulted in 304 possible manuscripts. We included manuscripts assessing laboratory collected biomarkers from urine, serum, cerebrospinal fluid, and saliva. After screening and review of the initial literature search results, a total of 75 manuscripts were included in the narrative review. CONCLUSION: The studies reviewed suggested that specific biomarkers may help identify those patients at risk of disease development and function as a prognostic indicator for disease progression and treatment response. However, additional research is necessary before specific recommendations can be made, and current clinical decision-making is modified.

Cross-Validation of the Foundation Pain Index with PROMIS-29 in Chronic Pain Patients.

PURPOSE: Discovery and validation of pragmatic biomarkers represent significant advancements in the field of pain management. Evaluating relationships between objective biomarkers and patient-reported outcomes (PROs) is an effective way to gain mechanistic insight into the potential role of biochemistry in chronic pain. The aim of this study was to validate the Foundation Pain Index (FPI) by evaluating associations between deranged biochemical function and PROMIS-29 domains in individuals living with chronic pain. PATIENTS AND METHODS: PROMIS-29 scores and FPI test results were obtained from 298 patients with chronic pain in this retrospective, observational study. Statistical analysis was performed using clinical test data to evaluate relationships between deranged biochemical function and quality of life measures across 8 universal domains. RESULTS: FPI scores significantly associated with multiple PROMIS-29 domains including physical function, impact score, fatigue, pain interference, and depression (P < 0.05). Moreover, specific analytes that comprise the FPI significantly correlated with PROMIS-29 domains, including 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) (P < 0.05). CONCLUSION: Cross-validation of the FPI with PROMIS-29 domains further supports the role of deranged biochemical function in the etiology of chronic pain. Objective identification of atypical biochemical function and subsequent correction holds tremendous promise for the non-opioid management of pain. Continued research efforts will aim to determine the impact of biochemical optimization in pre-surgical periods and post-surgical outcomes in patients with chronic pain.

Randomized Trial on the Clinical Utility of a Novel Biomarker Panel to Identify Treatable Determinants of Chronic Pain.

Millions suffer daily from chronic pain diagnosed anatomically and treated with opioids. Research shows that underlying nutritional, metabolic and oxidative stressors, which drive the development or worsening of chronic pain, are not diagnosed despite the fact that treatment of these primary pain pathways relieves pain and increases function. One of the main reasons for this gap in care is the lack of a simple diagnostic assay to help clinicians make these diagnoses. We examined the clinical utility of a urine-based pain biomarker panel. Primary care physicians were randomized into the test group and compared to controls. We measured their ability to make the diagnosis and treat a total of nine standardized patients, with common but challenging cases of chronic pain, over two rounds of data collection in a pre-post design using a fixed-effects model. Intervention doctors received educational materials on a novel pain biomarker panel after the baseline round and had access to biomarker test results. Provider responses were measured against evidence-based criteria. The two study arms at baseline provided similar, poor care for three different primary pain pathways: nutritional deficiencies (5.0% control versus 9.2% intervention treated, p = 0.208), metabolic abnormalities (1.0% control versus 0% for intervention treated, p = 0.314), and oxidative stress (1.2% control versus 0% intervention treated, p = 0.152). After the introduction 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. These diagnostic and treatment improvements were seen across all three case types, 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. Intervention doctors were also 75.1% more likely 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). This experimental study showed significant clinical utility of a validated pain biomarker panel that determines nutritional deficiencies, metabolic abnormalities and oxidative stressors that drive underlying treatable causes of pain. When integrated into routine primary care practice, this testing approach could considerably improve diagnostic accuracy and provide more targeted, non-opioid treatments for patients suffering from chronic pain.

Clinical Validation of a Multi-Biomarker Assay for the Evaluation of Chronic Pain Patients in a Cross-Sectional, Observational Study.

INTRODUCTION: Chronic pain assessment and post-treatment evaluation continues to be challenging due to a lack of validated, objective tools to measure patient outcomes. Validation of mechanistic pain biomarkers would allow clinicians to objectively identify abnormal biochemistry contributing to painful symptoms. METHODS: We describe the clinical validation of a multi-biomarker assay with algorithmic analysis known as the Foundation Pain Index (FPI) in diverse cohorts of chronic pain patients in a prospective, cross-sectional, observational validation study. Levels of 11 urinary pain biomarkers were measured and tabulated using a proprietary algorithm to generate FPI scores for chronic pain subjects (N = 153) and age- and sex-matched pain-free controls (N = 334). RESULTS: 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). CONCLUSIONS: Our 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 of patients. This test provides novel, reproducible, objective data which may pave the way for non-opioid therapeutic strategies to treat chronic pain.

Association of urinary concentrations of phthalate metabolites with quinolinic acid among women: A potential link to neurological disorders.

BACKGROUND: Quinolinic acid (QA), a neuroactive metabolite produced during tryptophan degradation, is implicated in the pathogenesis of several neurological disorders. Phthalates are structurally similar to QA, and exposure to phthalates has demonstrated increased QA production and excretion in rodent studies. We recently showed that very high exposure to dibutyl phthalate was associated with higher concentrations of urinary QA in men. However, no human studies examined the associations between background (low) phthalate exposures and QA. OBJECTIVES: To examine the associations of urinary concentrations of phthalate metabolites with QA. METHODS: Female participants (N = 126) who participated in a prospective cohort study at the Massachusetts General Hospital Fertility Center provided 758 urine samples (273 during pregnancy and 485 during non-pregnancy). Concentrations of 11 phthalate metabolites and QA in urine were measured. We used multivariable linear mixed effect models to estimate the percent change in urinary QA concentrations associated with a doubling (100%) of urinary phthalate metabolite concentration, and evaluated whether there was effect modification by pregnancy status. RESULTS: Women's mean (standard deviation) age was 34.2 (4.0) years with a body mass index of 23.5 (3.7) kg/m2. The women were primarily Caucasian (92%), had at least a college degree (98%), and none were current smokers. Pairwise Spearman correlations between concentrations for phthalate metabolites and QA measured in the same urine samples ranged from 0.36 for MEHP to 0.68 for dibutyl phthalate (DBP) metabolites. In multivariable-adjusted models, the percent change in urinary QA concentrations was significantly higher for each doubling of several urinary phthalate metabolite concentrations. For example, each doubling of DBP metabolites was associated with a 13.7% (95%CI: 10.6, 16.9)% higher QA. Associations between the low molecular weight phthalate metabolites and QA were stronger among samples collected during pregnancy as compared to non-pregnancy samples from the same women. CONCLUSIONS: Urinary concentrations of several phthalate metabolites were positively associated with QA among women. These findings, along with the known neurotoxicity of QA, warrant the need to examine whether QA concentrations may serve as a pathway for the adverse neurodevelopment outcomes found in children's health studies.

An Analysis of Biomarkers in Patients with Chronic Pain.

BACKGROUND: Because of the subjective nature of current pain assessments, limited efficacy of treatment options and risks associated with opioid abuse and diversion, the need for objective data to assist with chronic pain management has never been greater. Successful identification of mechanistic biomarkers would not only improve our understanding and ability to accurately diagnose pain disorders but would also facilitate the development of disease-modifying pain drugs. OBJECTIVES: The objective of this study was to determine and evaluate the prevalence of abnormal biomarker findings in a population of patients with chronic pain. STUDY DESIGN: Retrospective, observational study. SETTING: Data analysis of biomarker test results was performed at a single industry site (Ethos Research & Development, Newport, KY) from clinical samples collected and analyzed from July to December 2018. METHODS: A novel, pain-specific biomarker test panel that evaluates biomarkers of systemic inflammation, oxidative stress, neurotransmitter turnover, and micronutrient status was employed to determine the prevalence of abnormal findings in 17,834 unique patient samples analyzed at a national reference laboratory (Ethos Laboratories, Newport, KY). Patient biomarker results were considered abnormal if they were outside of the 95% confidence interval reference ranges established using a healthy population of donors who had no history of chronic pain or opioid use. RESULTS: A total of 77% of patients with chronic pain exhibited at least one abnormal biomarker result (n = 13,765). The most common abnormal biomarker finding was elevated quinolinic acid, which was observed in 29% of patients (n = 5,107). Elevated pyroglutamate, indicative of glutathione depletion, was observed in 19% of patients (n = 3,314). Elevated xanthurenic acid, indicative of vitamin B6 insufficiency, was observed in 17% of patients (3,025). Elevated levels of the acrolein metabolite 3-hydroxypropyl mercapturic acid were observed in 21% of patients (n = 3,667). Elevated methylmalonic acid, indicative of a vitamin B12 deficiency, was observed in 10% of patients (n = 1,827), whereas abnormally low levels of neurotransmitter metabolites were observed in 8% of patients (n = 1,456). LIMITATIONS: Medications and/or conditions other than those associated with chronic pain were not evaluated as potential causes of abnormal biomarker findings. CONCLUSIONS: A novel biomarker assay that measures objective correlates to the neurobiological processes underlying chronic pain reveals a high prevalence of atypical biochemistry in a population of patients with pain. Abnormal biomarker findings presented here provide objective support for the role of cytokine-mediated inflammation, oxidative stress, abnormally low production of neurotransmitters, and micronutrient deficiencies in the development or worsening of chronic pain. This unique panel of functional pain biomarkers provides practitioners with novel, objective insight into the underlying causes of pain, which will pave the way for truly personalized pain medicine. Correcting abnormal biomarker findings with targeted, nonopioid therapies to improve patient function and alleviate pain potentially could lessen the opioid burden and drastically reduce health care costs. KEY WORDS: Biomarker, pain, inflamation, oxidative stress, neurotransmitter, micronutrient deficiency, Kynurenine Pathway.

High phthalate exposure increased urinary concentrations of quinolinic acid, implicated in the pathogenesis of neurological disorders: Is this a potential missing link?

BACKGROUND: Quinolinic acid (QA), a neuroactive metabolite of the Kynurenine Pathway (KP), is an excitotoxin that is implicated in the pathogenesis of many neurological disorders. KP is the main tryptophan degradation pathway. Phthalates can structurally mimic tryptophan metabolites and diets containing phthalates in rats enhanced the production and excretion of QA. However, there are no human studies that have examined the association between phthalates and QA. OBJECTIVES: Taking advantage of different mesalamine formulations with/without dibutyl phthalate (DBP), we assessed whether DBP from mesalamine (>1000x background) altered the urinary concentrations of QA. METHODS: Men with inflammatory bowel disease participated in a prospective crossover pilot study. 15 Men were on non-DBP mesalamine (background) at baseline crossed-over for 4 months to high-DBP mesalamine (high) (B1H-Arm) and vice versa for 15 men who were on high-DBP mesalamine at baseline (H1B-Arm). Men provided 60 urine samples (2/man). We estimated crossover and cross-sectional changes in the creatinine normalized-QA using multivariable linear mixed effect models with random intercepts. RESULTS: At baseline, men who were on high-DBP mesalamine (H1B-Arm) had 72%, (95% confidence interval (CI): 18, 151) higher normalized-QA than men who were on background exposure and when high-DBP mesalamine was removed for four months, normalized-QA decreased with 32%, (95% CI: -45.0, -15.1). Consistently, when men in B1H-Arm were newly-exposed to high-DBP mesalamine, normalized-QA increased with 11%, (95% CI: -11, 38). CONCLUSIONS: High-DBP exposure from mesalamine increased the urinary concentrations of QA, which was largely reversed after removal of the high-DBP exposure for four months. This novel hypothesis should warrant new promising research considering the KP and QA concentrations as a plausible mediator for the neurotoxicity possibly linked with phthalate exposures.

Blood testing in chronic pain management.

Blood testing is quickly becoming a useful laboratory tool for opioid prescribers who wish to document and assess patient tolerance, more objectively monitor patient safety, and evaluate patient compliance using information that is not available with traditional urine drug testing (UDT). Blood testing does not need to be performed as frequently as UDT but provides extremely valuable information which can be used to more accurately evaluate patient compliance and assist with interpreting blood toxicology results commonly used in impairment or overdose cases. This narrative review presents the current evidence supporting the use of blood testing within the chronic pain management setting. In addition, this review aims to introduce and discuss the role of routine blood testing within the chronic pain management setting. Blood testing for the purpose of documenting opioid tolerance is a relatively novel tool for pain physicians and as such this review is not intended to be a comprehensive or exhaustive review of the scientific or medical literature. Prescribers must also be aware that this type of laboratory testing need only be administered to chronic pain patients receiving daily opioid therapy. Patients taking infrequent, low dose, or as needed medications are not anticipated to benefit from this type of test. Based on the complexity of both achieving acceptable outcomes with opioid treatment and the legal and societal issues at hand, we feel that the addition of blood concentration levels will become the standard of care in the near future.

Simultaneous quantification of amphetamine and methamphetamine in meconium using ISOLUTE HM-N-supported liquid extraction columns and GC-MS.

A procedure is described for the rapid extraction and quantification of amphetamine and methamphetamine from meconium using ISOLUTE HM-N-supported liquid extraction columns and gas chromatography-mass spectrometry (GC-MS). Because of the matrix complexity of meconium samples, extraction and sample preparation prior to instrumental analysis can prove difficult and time-consuming. The present study introduces a novel sample preparation technique for the simultaneous quantification of amphetamine and methamphetamine in meconium using GC-MS. Extraction of both analytes was achieved using ISOLUTE HM-N-supported liquid extraction columns containing a modified form of diatomaceous earth. Limits of detection for both analytes were 30 ng/g and the lower limit of quantitation was 75 ng/g. Linearity was achieved over the range 75-3000 ng/g. The methodology showed excellent intrarun precision with %CV values ranging from 2 to 8% for both analytes. Interrun precision experiments produced %CV values between 7 and 10% for both analytes. The reported methodology proved suitable for the accurate quantification of amphetamine and methamphetamine in meconium samples and greatly reduced the sample preparation time normally required for traditional solid-phase extraction. The development and validation of such analytical methodologies will prove beneficial for the identification of prenatal substance abuse, which is an ongoing concern across socioeconomic lines.

The determination of morphine in the larvae of Calliphora stygia using flow injection analysis and HPLC with chemiluminescence detection.

Selective determination of morphine in the larvae of Calliphora stygia (Fabricius) (Diptera: Calliphoridae) using acidic potassium permanganate chemiluminescence detection coupled with flow injection analysis and high-performance liquid chromatography (HPLC) is described. Larvae of C. stygia were reared on minced meat substrates that had been spiked with varying concentrations of morphine. Morphine concentrations were chosen to reflect typical levels in human tissues from opiate overdose victims. After maturing on substrates, larvae were analyzed for the presence of morphine using chemiluminescence detection coupled to flow injection analysis and a rapid HPLC method. Analysis of the larval matrix by flow injection analysis with chemiluminescence detection indicated the presence of interferants capable of generating chemiluminescence. A rapid chromatographic separation with a monolithic column allowed selective determination of morphine in larvae using postcolumn chemiluminescence detection. Larvae of C. stygia reared on substrates containing morphine at concentrations of 500 and 1000 ng/g did not sequester morphine at detectable concentrations. Larvae reared on substrates containing morphine concentrations of 2500, 5000, and 10,000 ng/g tested positive for the drug at concentrations of 765, 2720, and 3010 ng/g, respectively.