Candidate Genes and Proteomic Biomarkers of Serum and Urine in Medication-Overuse Headache.

Chronic headache is a topical problem of neurology, psychiatry and general practice. The medication-overuse headache (MOH) is one of the leading pathologies in the structure of chronic headache. However, early diagnosis of the MOH is challenging. We analyzed potential proteomic biomarkers of serum and urine in patients with MOH. METHODS: We searched PubMed, Springer, Scopus, Web of Science, ClinicalKey, and Google Scholar databases for English publications over the past 10 years using keywords and their combinations. RESULTS: We found and analyzed seven studies that met the search criteria for the purpose of the review, including 24 serum proteomic biomarkers and 25 urine proteomic biomarkers of MOH. Moreover, the candidate genes and locus of the studied serum (vitamin D-binding protein, lipocalin-type prostaglandin D2 synthase, apolipoprotein E, etc.) and urine proteomic biomarkers (uromodulin, alpha-1-microglobulin, zinc-alpha-2-glycoprotein, etc.) of MOH are presented in this review. CONCLUSIONS: The serum and urine proteomic biomarkers of MOH can potentially help with the identification of patients with MOH development. Due to the relevance of the problem, the authors believe that further investigation of the MOH proteomic biomarkers in different ethnic and racial groups of patients with primary headache is necessary. In addition, it is important to investigate whether medications of different drug classes influence the levels of serum and urine proteomic biomarkers.

Review of the Current State of Urine Drug Testing in Chronic Pain: Still Effective as a Clinical Tool and Curbing Abuse, or an Arcane Test?

PURPOSE OF REVIEW: Therapeutic use, misuse, abuse, and diversion of controlled substances in managing chronic non-cancer pain remain a major concern for physicians, the government, payers, and patients. The challenge remains finding effective diagnostic tools that can be clinically validated to eliminate or substantially reduce the abuse of controlled prescription drugs, while still assuring the proper treatment of those patients in pain. Urine drug testing still remains an important means of adherence monitoring, but questions arise as to its relevance and effectiveness. This review examines the role of UDT, determines its utility in current clinical practice, and investigates its relevance in current chronic pain management. RECENT FINDINGS: A review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Literature was searched from year 2000 to present examining the relevance and role of UDT in monitoring chronic opioid therapy along with reliability and accuracy, appropriate use, overuse, misuse, and abuse. There are only a limited number of reviews and investigations on UDT, despite the fact that clinicians who prescribe controlled medications for chronic states commonly are expected to utilize UDT. Therefore, despite highly prevalent use, there is a limited publication base from which to draw in this present study. Regardless of experience or training background, physicians and healthcare providers can much more adequately assess opioid therapy with the aid of UDT, which often requires confirmatory testing by a laboratory for clinical and therapeutic prescribing decisions. It has become a strongly recommended aspect of pain care with controlled substances locally, regionally, and nationally. Incorporating UDT for all patients in whom chronic opioid therapy is undertaken is consistent with state and national guidelines and best practice strategies. Practice standards vary as to the frequency of UDT locally, regionally, and nationally, however.

Association of Longitudinal Changes in Symptoms and Urinary Biomarkers in Patients with Urological Chronic Pelvic Pain Syndrome: A MAPP Research Network Study.

PURPOSE: We analyzed a series of novel noninvasive urinary biomarkers for their ability to objectively monitor the longitudinal clinical status of patients with urological chronic pelvic pain syndrome. MATERIALS AND METHODS: Baseline, 6 and 12-month urine samples were collected (216) and used to quantify vascular endothelial growth factor, vascular endothelial growth factor (VEGF) receptor 1 (R1), neutrophil gelatinase associated lipocalin (NGAL), matrix metalloproteinase-2, matrix metalloproteinase (MMP)-9, and MMP-9/NGAL complex by enzyme-linked immunosorbent assays. Patient symptom changes were classified as improved, stable or worse using a functional clustering algorithm. Proportional odds models were used to evaluate the association between symptom change and urinary biomarkers. RESULTS: Across all sampled participants, longitudinal decreases in normalized VEGF concentration (pg/µg) were associated with pain severity improvement, and decreases in MMP-9, NGAL and VEGF-R1 concentration (pg/ml) as well as NGAL normalized concentration were associated with improved urinary symptoms. Longitudinal decreases in normalized VEGF-R1 were associated with pain improvement in patients with moderate widespreadness, no bladder symptoms and no painful filling. Lower baseline normalized VEGF-R1 concentration was associated with pain improvement in patients with pelvic pain only. Higher baseline MMP-9/NGAL levels were associated with pain and urinary improvement across all participants. Moreover, longitudinal increases in MMP-2 concentration was associated with improved pain in men and patients with painful filling. CONCLUSIONS: Our results suggest these urinary biomarkers may be useful in monitoring urological chronic pelvic pain syndrome symptom changes with respect to both urinary severity and pain severity. With further testing, they may represent objective biological measures of urological chronic pelvic pain syndrome progression and/or resolution while also providing insight into the pathophysiology of urological chronic pelvic pain syndrome.

Culture-independent Next Generation Sequencing of Urine and Expressed Prostatic Secretions in Men With Chronic Pelvic Pain Syndrome.

OBJECTIVE: To compare standard cultures and next-generation sequencing (NGS) in men with chronic prostatitis/chronic pelvic pain syndrome (CPPS). CPPS shares clinical features with urinary tract infections, but bacteria are seldom found. NGS is more sensitive than standard cultures. MATERIALS AND METHODS: Men diagnosed with CPPS (National Institute of Health Category III) underwent traditional cultures and NGS of their urine and expressed prostatic secretions (EPS). Characteristics between groups were compared statistically. RESULTS: Thirty-one men with CPPS were included (mean age 44.5). All standard urine cultures were negative, and 3 EPS cultures were positive. Seventy-eight unique microbes were detected with NGS, including uropathogens in 10 of the men. There were no bacteria identified by NGS in EPS that were not also found in the urine. Men with positive NGS did not differ from those without in age, symptom severity or phenotype. Men with typical urinary tract infection symptoms (eg, dysuria, chills) were more likely to have uropathogens detected on NGS relative to men without such symptoms. Nine patients were prescribed antibiotics based on their NGS findings, but only 1 exhibited symptom improvement (11%). CONCLUSION: NGS commonly identified bacteria in CPPS patients, but these did not localize to the prostate. NGS positivity did not correlate with symptom severity and antibiotic therapy was seldom effective. NGS detected uropathogens more frequently in those with clinical symptoms suggestive of urinary tract infection. Clinical trials are needed to examine the utility of NGS-guided antibiotics in this subpopulation.

Clinician Response to Aberrant Urine Drug Test Results of Patients Prescribed Opioid Therapy for Chronic Pain.

OBJECTIVE: Urine drug testing (UDT) is recommended for patients who are prescribed opioid medications, but little is known about the various strategies clinicians use to respond to aberrant UDT results. We sought to examine changes in opioid prescribing and implementation of other risk reduction activities following an aberrant UDT. METHODS: In a national cohort of Veterans Affairs patients with new initiations of opioid therapy through 2013, we identified a random sample of 100 patients who had aberrant positive UDTs (results positive for nonprescribed/illicit substance), 100 who had aberrant negative UDTs (results negative for prescribed opioid), and 100 who had expected UDT results. We examined medical record data for opioid prescribing changes and risk reduction strategies in the 12 months following UDT. RESULTS: Following an aberrant UDT, 17.5% of clinicians documented planning to discontinue or change the opioid dose and 52.5% initiated another strategy to reduce opioid-related risk. In multivariate analyses, variables associated with a planned change in opioid prescription status were having an aberrant positive UDT (odds ratio [OR], 30.77; 95% confidence interval [CI], 5.92-160.10) and higher prescription opioid dose (OR, 1.01; 95% CI, 1.01-1.02). The only variable associated with implementation of other risk reduction activities was having an aberrant positive UDT (OR, 0.29; 95% CI, 0.16-0.55). DISCUSSION: The majority of clinicians enacted some type of opioid prescribing or other change to reduce risk following an aberrant UDT, and the action depended on whether the result was an aberrant positive or aberrant negative UDT. Experimental studies are needed to develop and test strategies for managing aberrant UDT results.

Changes in brain white matter structure are associated with urine proteins in urologic chronic pelvic pain syndrome (UCPPS): A MAPP Network study.

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network has yielded neuroimaging and urinary biomarker findings that highlight unique alterations in brain structure and in urinary proteins related to tissue remodeling and vascular structure in patients with Urological Chronic Pelvic Pain Syndrome (UCPPS). We hypothesized that localized changes in diffusion tensor imaging (DTI) measurements might be associated with corresponding changes in urinary protein levels in UCPPS. To test this hypothesis, we created statistical parameter maps depicting the linear correlation between DTI measurements (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) and urinary protein quantification (MMP2, MMP9, NGAL, MMP9/NGAL complex, and VEGF) in 30 UCPPS patients from the MAPP Research Network, after accounting for clinical covariates. Results identified a brainstem region that showed a strong correlation between both ADC (R2 = 0.49, P<0.0001) and FA (R2 = 0.39, P = 0.0002) with urinary MMP9 levels as well as a correlation between both ADC (R2 = 0.42, P = 0.0001) and FA (R2 = 0.29, P = 0.0020) and urinary MMP9/NGAL complex. Results also identified significant correlations between FA and urinary MMP9 in white matter adjacent to sensorimotor regions (R2 = 0.30, P = 0.002; R2 = 0.36, P = 0.0005, respectively), as well as a correlation in similar sensorimotor regions when examining ADC and urinary MMP2 levels (R2 = 0.42, P<0.0001) as well as FA and urinary MMP9/NGAL complex (R2 = 0.33, P = 0.0008). A large, diffuse cluster of white matter was identified as having a strong correlation between both ADC (R2 = 0.35, P = 0.0006) and FA (R2 = 0.43, P<0.0001) with urinary NGAL levels. In contrast, no significant association between DTI measurements and VEGF was observed. Results suggest that elevated MMP9 or MMP9/NGAL in UCPPS may be related to degenerative neuronal changes in brainstem nuclei through excitotoxicity, while also facilitating synaptic plasticity in sensorimotor regions.

Predictors of pain, urinary symptoms and quality of life in patients with chronic pelvic pain syndrome (CPPS): A prospective 12-month follow-up study.

OBJECTIVE: Chronic pelvic pain syndrome (CPPS) can affect both men and women and often causes substantial impairment to quality of life. Although cross-sectional studies have suggested that psychosocial aspects may constitute important factors in the etiology and maintenance of CPPS, longitudinal studies are rare. Therefore, the present study examines psychosocial factors as prospective predictors of pain intensity, urinary symptoms and impediments to quality of life in men and women with CPPS. METHODS: Data were collected from patients during visits to a specialized, interdisciplinary outpatient clinic and after 12 months. Outcomes included pain intensity, urinary symptoms and impediments to quality of life, all of which were measured with the NIH-CPSI. Age, sex, depressive-anxious symptomatology (PHQ-ADS), pain catastrophizing (PCS), health anxiety (WI-7) and social support (FSozU) were examined as predictors in multivariate linear regressions. RESULTS: Data from 109 patients (59.6% female; age M = 49.3, SD = 16.7) were analyzed. Pain severity (ß = .30, p = .004), age (ß = .22, p = .02), urinary symptoms (ß = .24, p = .01) and depressive-anxious symptomatology (ß = .29, p = .009) at baseline emerged as predictors of pain at follow-up. Urinary symptoms were predicted by urinary symptoms (ß = .53, p < .001) and depressive-anxious symptomatology (ß = .25, p = .01) at baseline; impediments to quality of life were predicted by depressive-anxious symptomatology (ß = .27, p = .01). CONCLUSION: Psychological factors, especially depressive-anxious symptomatology, predict CPPS-specific symptom severity and impediments to quality of life after 12 months and thus substantially contribute to the chronification of CPPS. It is recommended to address anxiety and depression in patients with CPPS as early as possible in biopsychosocially oriented treatment approaches.

Opioid tolerance and urine drug testing among initiates of extended-release or long-acting opioids in Food and Drug Administration's Sentinel System.

OBJECTIVE: A risk evaluation and mitigation strategy for extended-release and long-acting (ER/LA) opioid analgesics was approved by the Food and Drug Administration in 2012. Our objective was to assess frequency of opioid tolerance and urine drug testing for individuals initiating ER/LA opioid analgesics. DESIGN: Retrospective cohort study. SETTING: Sentinel, a distributed database with electronic healthcare data on >190 million predominantly commercially insured members. PATIENTS, PARTICIPANTS: Members under age 65 initiating ER/LA opioid analgesics between January 2009 and December 2013. MAIN OUTCOME MEASURE(S): We examined the proportion of opioid-tolerant-only ER/LA opioid analgesic initiates meeting tolerance criteria: receipt of ≥30 mg oxycodone equivalents per day in 7 days prior to the first opioid-tolerant-only dispensing. We separately examined the proportion of new users of extended-release oxycodone (ERO) and other ER/LA opioid analgesics with a claim for a urine drug test in the 30 days prior to, and separately for the 183 days after, dispensing. RESULTS: We identified 79,824 ERO, 7,343 extended-release hydromorphone, and 91,778 transdermal fentanyl opi-oid-tolerant-only episodes. Tolerance criteria were met in 64 percent of ERO, 64 percent of extended-release hydromorphone and 40 percent of transdermal fentanyl episodes. We identified 210,581 incident ERO and 311,660 other ER/LA opioid analgesic episodes. Use of urine drug testing for ERO compared with other ER/LA opioid analgesics was: 4 percent vs 14 percent respectively in the 30 days prior to initiation and 9 percent vs 23 percent respectively in the 183 days following initiation. CONCLUSIONS: These results suggest potential areas for improving appropriate ER/LA opioid analgesic prescribing practices.

Five lessons learned about long-term pain management in adults with sickle cell disease.

Chronic pain affects one-half of adults with sickle cell disease (SCD). Despite the prevalence of chronic pain, few studies have been performed to determine the best practices for this patient population. Although the pathophysiology of chronic pain in SCD may be different from other chronic pain syndromes, many of the guidelines outlined in the pain literature and elsewhere are applicable; some were consensus-adopted in the 2014 National Heart, Lung, and Blood Institute SCD Guidelines. Recommended practices, such as controlled substance agreements and monitoring of urine, may seem unnecessary or counterproductive to hematologists. After all, SCD is a severe pain disorder with a clear indication for opioids, and mistrust is already a major issue. The problem, however, is not with a particular disease but with the medicines, leading many US states to pass broad legislation in attempts to curb opioid misuse. These regulations and other key tenets of chronic pain management are not meant to deprive adults with SCD of appropriate therapies, and their implementation into hematology clinics should not affect patient-provider relationships. They simply encourage prudent prescribing practices and discourage misuse, and should be seen as an opportunity to more effectively manage our patient's pain in the safest manner possible. In line with guideline recommendations as well as newer legislation, we present five lessons learned. These lessons form the basis for our model to manage chronic pain in adults with SCD.

Urinary Concentrations of Topically Administered Pain Medications.

A common treatment for chronic pain is prescription of analgesics, but their long-term use entails risk of morbidity, addiction and misuse. One way to reduce the risk of abuse is prescribing of analgesics in a topical form. Physicians are urged to perform urine drug testing to ensure that patients are compliant with their medication regimens. However, there is little data on the efficiency of transdermal delivery for many analgesic drugs, and no data on expected urine drug levels. This study includes data from over 29,000 specimens tested for gabapentin, ketamine, cyclobenzaprine or amitriptyline used orally or topically. Gabapentin and amitriptyline concentrations were more likely to be below the limits of detection (25-40 ng/mL) in the urine of patients using them topically as compared with patients using them orally. Levels in gabapentin-positive topical specimens were much lower than in gabapentin-positive oral specimens (261 ng/mL vs >10,000 ng/mL). In contrast, ketamine and cyclobenzaprine were more readily detectable in the urine of topical users. Ketamine topical specimens were positive 12% more often than oral specimens, and mean topical specimen levels were 68-100% those of oral specimens. Cyclobenzaprine specimens were equally likely to be positive whether the dose was oral or topical, although mean levels after topical dosing were approximately 13-21% those after oral dosing. These findings are consistent with the reported percutaneous absorption efficiencies of gabapentin and ketamine, and are likely to be related to the absorption efficiencies of cyclobenzaprine and amitriptyline.

Repeated Quantitative Urine Toxicology Analysis May Improve Chronic Pain Patient Compliance with Opioid Therapy.

BACKGROUND: Even though serious efforts have been undertaken by different medical societies to reduce opioid use for treating chronic benign pain, many Americans continue to seek pain relief through opioid consumption. Assuring compliance of these patients may be a difficult aspect of proper management even with regular behavioral monitoring. OBJECTIVE: The purpose of this study was to accurately assess the compliance of chronic opioid-consuming patients in an outpatient setting and evaluate if utilizing repeated urine drug testing (UDT) could improve compliance. STUDY DESIGN: Retrospective analysis of prospectively collected data. SETTING: Outpatient pain management clinic. METHODS: After Institutional Review Board (IRB) approval, a retrospective analysis of data for 500 patients was conducted. We included patients who were aged 18 years and older who were treated with opioid analgesic medication for chronic pain. Patients were asked to provide supervised urine toxicology specimens during their regular clinic visits, and were asked to do so without prior notification. The specimens were sent to an external laboratory for quantitative testing using liquid chromatography-tandem mass spectrometry. RESULTS: Three hundred and eighty-six (77.2%) patients were compliant with prescribed medications and did not use any illicit drugs or undeclared medications. Forty-one (8.2%) patients tested positive for opioid medication(s) that were not prescribed in our clinic; 8 (1.6%) of the patients were positive for medication that was not prescribed by any physician and was not present in the Illinois Prescription Monitoring Program; 5 (1%) patients tested negative for prescribed opioids; and 60 (12%) patients were positive for illicit drugs (8.6% marijuana, 3.2% cocaine, 0.2% heroin). Repeated UDTs following education and disclosure, showed 49 of the 77 patients (63.6%) had improved compliance. LIMITATIONS: This was a single-site study and we normalized concentrations of opioids in urine with creatinine levels while specific gravity normalization was not used. CONCLUSIONS: Our results showed that repeated UDT can improve compliance of patients on opioid medications and can improve overall pain management. We believe UDT testing should be used as an important adjunctive tool to help guide clinical decision-making regarding opioid therapy, potentially increasing future quality of care.Key words: Urine toxicology analysis, chronic pain, opioids, compliance, pain management, urine drug testing, urine drug screening.

Toxicology in Pain Management.

Toxicology testing in pain management has become the standard of care. The Center for Disease Control and Prevention published guidelines including urine drug testing prior to initiating opioid therapy and for monitoring prescription and illicit drugs. Physicians must know indications for toxicology testing, and the frequency based upon risk stratification. This includes personal and family history of alcohol or substance related disorders, mental illness and smoking. Knowledge of opioid metabolism and various matrices to test are described. Additional knowledge of presumptive vs definitive testing along with algorithms and medical necessity with evidence-based clinical standards are discussed.

Impact of Urine Drug Screening on No Shows and Dropouts among Chronic Pain Patients: A Propensity-Matched Cohort Study.

BACKGROUND: The last 2 decades have seen a substantial increase in both the prescription of opioids for managing chronic pain, and an increase in opioid-related deaths in the US. Urine drug screening (UDS) is the de facto monitoring tool aimed at detecting and deterring opioid misuse. OBJECTIVE: We study whether administering UDS on pain patients influences post-screening behavior of no-shows and dropouts. STUDY DESIGN: Observational cohort study of electronic medical records. SETTING: Single urban academic pain-clinic. METHODS: A retrospective cohort comparison of patients receiving UDS versus those not receiving UDS was conducted on the entire sample as well as in the propensity score-matched samples in which matching was based on age, gender, pain-score, procedure-scheduled, systolic and diastolic blood pressure (BP), pulse, temperature, physician ID, year of visit, psychology referral, and opioid prescription in the first visit. In addition, we conducted within-subjects logistic-regression to study no-shows and non-proportional hazards survival modeling to study dropout. RESULTS: Analyses of 4,448 clinic visits by 723 pain patients indicated that UDS exposure in the first visit is associated with increased risk of no-show in the second visit (OR = 2.73, P < .0001); no-show rate was 10.24% for those without UDS compared to 23.75% for those with a UDS. Among those tested, the no-show rate was higher for those testing positive for illicit substances (34.57%) than for those testing negative (21.74%). These findings were replicated in 8 different propensity-score matched subsamples aimed at addressing potential non-random selection, as well as in within-subject analysis accounting for individual-level no-show propensity. Non-proportional hazards survival analysis shows that risk of dropout increased by 100.3% with every additional UDS (HR 95% CI: 1.54 to 2.61). LIMITATIONS: Retrospective design, non-randomized sample, single-setting. CONCLUSIONS: The results indicate that UDS is associated with increased no-shows and dropout from clinic subject to limitations of observational studies such as selection bias and confound by unobserved variables. These results serve as a call for additional prospective randomized studies to understand the impact of UDS, and where the patients might go when they dropout from the clinic.

Predictors of urine drug testing for patients with chronic pain: Results from a national cohort of U.S. veterans.

BACKGROUND: Urine drug testing (UDT) is recommended for all patients who initiate chronic opioid therapy (COT) for the treatment of chronic pain; however, it is infrequently utilized. Some prior research has identified factors that may predict UDT, but studies have been limited. The purpose of this study is to examine the rate and predictors of UDT among a national sample of patients with chronic pain who had new initiations of COT. METHODS: Administrative data were examined for all veterans receiving medical care at Department of Veterans Affairs medical facilities who had new initiations of chronic opioid therapy (COT) during fiscal year 2011. RESULTS: Nineteen percent of patients who had new initiations of COT for chronic noncancer pain received UDT within 90 days of starting opioids. In adjusted analyses, patient-level factors that predicted increased likelihood of UDT included male gender (risk ratio [RR] = 1.23, 95% confidence interval [CI] = 1.02-1.49), Black race (RR = 1.20, 95% CI = 1.06-1.37), divorced/separated marital status (RR = 1.13, 95% CI = 1.02-1.25), higher pain intensity (RR = 1.03, 95% CI = 1.01-1.05), comorbid substance use disorder (RR = 1.42, 95% CI = 1.27-1.60), posttraumatic stress disorder (PTSD) (RR = 1.14, 95% CI = 1.01-1.29), bipolar disorder or schizophrenia (RR = 1.29, 95% CI = 1.08-1.53), having received UDT prior to initiating opioid therapy (RR = 1.43, 95% CI = 1.26-1.62), and a higher baseline opioid dose (RR = 1.38-1.81, 95% CIs = 1.20-1.58, 1.57-2.09). Age was also associated with UDT, in a nonlinear manner. Several factors were associated with lower likelihood of UDT, including living in a highly rural setting (RR = 0.62, 95% CI = 0.29-0.99), having a VA service-connected disability (RR = 0.85-0.89, 95% CIs = 0.75-0.97, 0.79-0.99), and having a nurse practitioner or physician assistant as one's primary care clinician (RR = 0.72, 95% CI = 0.61-0.85). CONCLUSIONS: Urine drug testing was conducted with 19% of patients who had new initiations of COT. Factors that predicted UDT were multifaceted and included patient and clinician variables. Multidimensional system-level interventions may be needed to facilitate widespread implementation of UDT.

Primary care providers' experiences with urine toxicology tests to manage prescription opioid misuse and substance use among chronic noncancer pain patients in safety net health care settings.

BACKGROUND: Guideline recommendations to reduce prescription opioid misuse among patients with chronic noncancer pain include the routine use of urine toxicology tests for high-risk patients. Yet little is known about how the implementation of urine toxicology tests among patients with co-occurring chronic noncancer pain and substance use impacts primary care providers' management of misuse. Clinicians' perspectives on the benefits and challenges of implementing urine toxicology tests in the monitoring of opioid misuse and substance use in safety net health care settings are presented in this paper. METHODS: Twenty-three primary care providers from 6 safety net health care settings whose patients had a diagnosis of co-occurring chronic noncancer pain and substance use were interviewed. Interviews were transcribed, coded, and analyzed using grounded theory methodology. RESULTS: The benefits of implementing urine toxicology tests for primary care providers included less reliance on intuition to assess for misuse and the ability to identify unknown opioid misuse and/or substance use. The challenges of implementing urine toxicology tests included insufficient education and training about how to interpret and implement tests, and a lack of clarity on how and when to act on tests that indicated misuse and/or substance use. CONCLUSIONS: These data suggest that primary care clinicians' lack of education and training to interpret and implement urine toxicology tests may impact their management of patient opioid misuse and/or substance use. Clinicians may benefit from additional education and training about the clinical implementation and use of urine toxicology tests. Additional research is needed on how primary care providers implementation and use of urine toxicology tests impacts chronic noncancer pain management in primary care and safety net health care settings among patients with co-occurring chronic non cancer pain and substance use.

Simultaneous Quantitation of 78 Drugs and Metabolites in Urine with a Dilute-And-Shoot LC-MS-MS Assay.

A novel LC-MS-MS assay that simultaneously detects and quantitates 78 drugs and metabolites was developed and validated for chronic pain management. Urine specimen was diluted and mixed with internal standards (ISs) before injected into LC-MS-MS. Seventy-two analytes were detected with positive electrospray ionization mode and the remaining six analytes with negative mode. Two separate gradient elution chromatographic programs were established with the same mobile phases on the same bi-phenyl HPLC column. The assay was linear for all analytes with linear regression coefficient ranging 0.994-1.000. The intra-assay precision was between 1.7 and 8.8% and inter-assay precision between 1.9 and 12.2%, with bias <20% for all but six analytes. All analytes in urine specimens were stable for 7 days at 4°C, and no significant matrix effect or carryover was observed. A suboptimal recovery rate (60.0-156.8%) was observed for six analytes, potentially due to the lack of available deuterated ISs, requiring comparison to a chemically different IS. Method comparison using patient and proficiency testing samples demonstrated that this assay was sensitive and accurate. The assay improves on currently existing assays by including glucuronide conjugates, allowing direct detection of metabolites that might otherwise be missed by existing methods.

Interpretation of urine drug testing results in patients using transdermal buprenorphine preparations for the treatment of chronic noncancer pain.

OBJECTIVE: To determine whether the prevailing liquid chromatography and tandem mass spectroscopy assay (LC-MS/MS) assay designed to monitor buprenorphine compliance of the sublingual formulation used in the substance abuse treatment setting can be extrapolated to the transdermal formulation used in the chronic pain treatment setting, which is 1000-fold less concentrated. DESIGN: Retrospective chart review. SUBJECTS: Self-reported compliant patients using the transdermal or sublingual formulations of buprenorhphine. Transdermal patch application was also visually confirmed during clinic visits. METHODS: Urine drug test results from a LC-MS/MS were compared between samples from transdermal and sublingual patients. RESULTS: While all sublingual patients tested positive for at least one metabolite of buprenorphine, only 69% of the transdermal patients did so. In addition, the most abundant metabolite in the transdermal patients was buprenorphine-glucuronide, as compared with norbuprenorphine-glucuronide in sublingual patients. CONCLUSIONS: These data suggest that currently available urine drug tests for buprenorphine, including the more expensive LC-MS/MS based assays, may not be sufficiently sensitive to detect the metabolites from transdermal buprenorphine patients. This study highlights the need to evaluate the value and sensitivity of urine drug tests given the wide range of buprenorphine dosing in clinical practice. These results underscore the need for additional cost benefit analyses comparing different confirmatory drug testing techniques including many commercially available drug testing options. © 2014 Wiley Periodicals, Inc.

Immunoassay in healthcare testing applications.

Immunoassay is used extensively for drug testing in pain management. Drug testing for the purpose of compliance monitoring is fundamentally different from forensic applications, which may rely on immunoassay screening to rapidly identify "negative" samples. In clinical settings, focus is shifted from identification of select drugs of abuse with low positivity rates to detection of a wide variety of licit and illicit compounds with expected high positivity rates. The primary drug classes of interest in this population, opioids and benzodiazepines, require special testing considerations when immunoassay is used. This review highlights the performance characteristics of immunoassay, with special emphasis on prescription drug classes and testing at the point-of-care.