Profiles of Urine Drug Test in Clinical Pain Patients vs Pain Research Study Subjects.

OBJECTIVE: To examine similarities and differences in urine drug test (UDT) results in clinical pain patients and pain subjects participating in pain research studies. DESIGN: An observational study with retrospective chart review and data analysis. METHODS: We analyzed 1,874 UDT results obtained from 1) clinical pain patients (Clinical Group; n = 1,529) and 2) pain subjects consented to participate in pain research studies (Research Group; n = 345). Since several medications such as opioids used in pain management are drugs of abuse (DOA) and can result in a positive UDT, we specifically identified those cases of positive UDT due to nonprescribed DOA and designated these cases as positive UDT with DOA (PUD). RESULTS: We found that 1) there was a higher rate of PUD in clinical pain patients (41.3%) than in pain research study subjects (14.8%); 2) although subjects in the Research Group were informed ahead of time that UDT will be conducted as a screening test, a substantial number (14.8%) of pain research study subjects still showed PUD; 3) there were different types of DOA between clinical pain patients (cannabinoids as the top DOA) and research study subjects (cocaine as the top DOA); and 4) a common factor associated with PUD was opioid therapy in both Clinical Group and Research Group. CONCLUSION: These results support previous findings that PUD is a common finding in clinical pain patients, particularly in those prescribed opioid therapy, and we suggest that UDT be used as routine screening testing in pain research studies.

The clinical impact of a false-positive urine cocaine screening result on a patient's pain management.

BACKGROUND: The urine of a patient admitted for chest and epigastric pain tested positive for cocaine using an immunoassay-based drug screening method (positive/negative cutoff concentration 150 ng/mL). Despite the patient's denial of recent cocaine use, this positive cocaine screening result in conjunction with a remote history of drug misuse impacted the patient's recommended pain therapy. Specifically, these factors prompted the clinical team to question the appropriateness of opioids and other potentially addictive therapeutics during the treatment of cancer pain from previously undetected advanced pancreatic carcinoma. OBJECTIVE: After pain management and clinical pathology consultation, it was decided that the positive cocaine screening result should be confirmed by gas chromatography-mass spectrometry (GC-MS) testing. RESULTS: This more sensitive and specific analytical technique revealed that both cocaine and its primary metabolite benzoylecgonine were undetectable (i.e., less than the assay detection limit of 50 ng/mL), thus indicating that the positive urine screening result was falsely positive. With this confirmation, the pain management service team was reassured in offering intrathecal pump (ITP) therapy for pain control. ITP implantation was well tolerated, and the patient eventually achieved excellent pain relief. However, ITP therapy most likely would not have been utilized without the GC-MS confirmation testing unless alternative options failed and extensive vigilant monitoring was initiated. CONCLUSION: As exemplified in this case, confirmatory drug testing should be performed on specimens with unexpected immunoassay-based drug screening results. To our knowledge, this is the first report of a false-positive urine cocaine screening result and its impact on patient management.

Urinary CTX-II concentrations are elevated and associated with knee pain and function in subjects with ACL reconstruction.

OBJECTIVE: Post-traumatic knee osteoarthritis (OA) is prevalent after anterior cruciate ligament reconstruction (ACLR). Biomarkers that identify individuals likely to develop OA, especially symptomatic OA, can help target preventative and therapeutic strategies. This study examined the magnitude and change over time in urinary CTX-II (uCTX-II) concentrations shortly after ACL reconstruction, and, secondarily, the associations with knee pain and function. DESIGN: Subjects were 28 patients with ACLR and 28 age- and sex-matched controls (CNTRL). Testing was conducted at four time points spaced 4 weeks apart (4, 8, 12 and 16 weeks post-operative in ACLR). Measures included demographics, urine samples, Numeric Pain Rating Scale (NPRS) and International Knee Documentation Committee Subjective Knee Form (IKDC-SKF). uCTX-II concentrations were determined with competitive enzyme-linked immunosorbent assay (ELISA). uCTX-II concentrations at each time point in ACLR were compared to the mean concentration over time in CNTRL, with and without adjustment for body mass index (BMI). Changes over time in each measure and correlations between the slopes of change were examined. RESULTS: uCTX-II concentrations were significantly higher in ACLR than CNTRL through 16 weeks post-operative when adjusted for BMI. In ACLR, uCTX-II concentrations significantly decreased over time, and the slope was associated with NPRS (r = 0.406, P = 0.039) and IKDC-SKF (r = -0.402, P = 0.034) slopes. CONCLUSION: uCTX-II concentrations shortly after ACLR were elevated compared to CNTRL and declined over time. Decreasing uCTX-II concentrations were associated with decreasing knee pain and improving function. uCTX-II may have a role as a prognostic marker following ACLR and warrants further investigation.

Recommendations for urine drug monitoring as a component of opioid therapy in the treatment of chronic pain.

OBJECTIVE: Several prominent guidelines recommend that patients on long-term opioid therapy have periodic urine drug monitoring (UDM) for appropriate use; however, none address the specific questions of which patients to test, which substances to test for, how often to test, and how to act on the results. DESIGN: In the absence of adequate scientific evidence in the literature, a panel of experts in the field of pain and addiction medicine was convened to develop consensus UDM recommendations. The panel met three times between March 2010 and April 2011, and reviewed several drafts of the recommendations document between meetings. RESULTS: The group was able to achieve consensus on a set of UDM recommendations addressing test selection, test frequency, interpretation of results, and how to handle discrepancies based on specific results. CONCLUSION: While the participating panel members recognize that there currently is a limited evidence base to support the expert panel's recommendations, primary care providers and pain specialists are largely acting today based on anecdote, intuition, and individual experience. The recommendations are meant to begin to provide a framework for standardizing practices for UDM in the treatment of chronic pain, and to serve as a catalyst to advance research that quantifies the effects of UDM on opioid therapy management and patient outcomes.

Interpretation of urine drug testing in pain patients.

BACKGROUND: Traditionally, urine drug screens have only been concerned with positive or negative results. Those results provide physicians treating patients for pain with chronic opioid therapy with information about medication compliance, use of nonprescribed medications, and use of illicit drugs. However, the analysis of urine for drugs offers additional information that, when compiled and accurately interpreted, may also be of great value to these doctors. PURPOSE: The aim of this article was to discuss the interpretation of urine drug tests and their application to pain physician practices. METHOD: We utilized a selection of recent articles on urine drug screening applicable to the pain patient population. RESULTS AND CONCLUSIONS: The article provides pertinent information about interpretation of urine drug testing, which is separated into six categories: which drugs and metabolites to test for; which analytical cutoffs to use; pain medication metabolism; identification of alcohol use; determination of patient compliance; and which patient groups to consider for more frequent testing.

Detection and quantification of tricyclic antidepressants and other psychoactive drugs in urine by HPLC/MS/MS for pain management compliance testing.

A sensitive, specific, and rapid high-pressure liquid chromatography/mass spectrometry/mass spectrometry method was developed for the quantitation of 11 tricyclic antidepressants and/or their metabolites; fluoxetine and norfluoxetine; cyclobenzaprine; and trazodone in urine. Samples were alkalinized with 0.2 N NaOH and extracted into 2 ml of hexane: ethyl acetate (1:1), evaporated to dryness, and reconstituted with 100 µl of 20 mM ammonium formate: methanol (20:80). The chromatographic separation was performed using an Allure Biphenyl 100 × 3.2 mm, 5-µ column with a mobile phase consisting of 20 mM ammonium formate: methanol (20:80 v/v) at a flow rate of 0.5 ml/min. The detection was accomplished by multiple-reaction monitoring via electrospray ionization source operating in the positive ionization mode. The calibration curve was linear over the investigated concentration range, 25-2,000 ng/ml, for each analyte using 1.0 ml of urine. The lower limit of quantitation for each analyte was 25 ng/ml. The intra- and inter-day precisions had coefficient of variation less than 15% and the accuracy was within the range from 88% to 109%. The method proved adequate for the tricyclic antidepressants analysis of urine for emergency clinical toxicology and pain management compliance testing.

Simultaneous quantification of 19 drugs/metabolites in urine important for pain management by liquid chromatography-tandem mass spectrometry.

BACKGROUND: Monitoring pain management drugs and frequently abused drugs is important for physicians to assess patient compliance. Liquid chromatography-tandem mass spectrometry offers high specificity needed for this purpose. In this report, a novel liquid chromatography-tandem mass spectrometry method for simultaneously monitoring 19 drugs/metabolites in urine was developed and validated. METHODS: Sample preparation included hydrolysis, dilution and turbulent flow online extraction. Analysis was achieved by reverse phase liquid chromatography and triple-quadruple tandem mass spectrometry. Two fragment ions, one for quantification and the other for assuring identification, were monitored for each analyte. RESULTS: No matrix effect or interference was observed. Lower limits of quantification ranged from 5 to 25 ng/mL. Within the linear range, analytical recovery was between 85.8% and 119.4%. Intra-assay and total coefficient of variations were between 0.2% and 12.7%. This method was compared with mass spectrometry methods offered by two other laboratories using 82 patient samples and 60 spiked urine samples showing 60%-100% agreement. The current method identified more positive samples for all analytes except THCA. The discrepancy in detection rates was primarily due to the different cut-offs used by the other laboratories. CONCLUSIONS: A sensitive and specific liquid chromatography-tandem mass spectrometry method was developed for measuring 19 drugs/metabolites in urine important for pain management clinics.

Sleep symptoms during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

STUDY OBJECTIVES: Describe the severity of getting to sleep, nighttime awakening, and early morning awakening across the menopausal transition (MT) and early postmenopause (PM) and their relationship to age, menopausal transition factors, symptoms, stress-related factors, and health related factors. DESIGN: Cohort. SETTING: community. PARTICIPANTS: 286 women from the Seattle Midlife Women's Health Study cohort. MEASUREMENTS: Participants completed annual menstrual calendars for MT staging, diaries in which they rated their symptoms, stress levels, and perceived health multiple times per year from 1990-2007 and provided first morning urine samples assayed for E1G, FSH, cortisol, and catecholamines. Multilevel modeling (R program) was used for data analysis. RESULTS: Severity of self-reported problems going to sleep was associated with all symptoms, perceived stress, history of sexual abuse, perceived health (-), alcohol use (-) (all P < 0.001), and lower cortisol (P = 0.009), but not E1G or FSH. Severity of nighttime awakening was significantly associated with age, late MT stage, and early PM, FSH, E1G (-), hot flashes, depressed mood, anxiety, joint pain, backache, perceived stress, history of sexual abuse, perceived health (-), and alcohol use (-) (all P < 0.001, except E1G for which P = 0.030). Severity of early morning awakening was significantly associated with age, hot flashes, depressed mood anxiety, joint pain, backache, perceived stress, history of sexual abuse, perceived health (-) (all P < or = 0.001, except E1G for which P = 0.02 and epinephrine (P = 0.038), but not MT stages or FSH. Multivariate models for each symptom included hot flashes, depressed mood, and perceived health. CONCLUSION: Sleep symptoms during the MT may be amenable to symptom management strategies that take into account the symptom clusters and promote women's general health rather than focusing only on the MT.

The role of urine drug testing for patients on opioid therapy.

Opioid analgesics must be prescribed with discernment and their appropriate use should be periodically assessed. Urine drug testing, although not designed specifically for this role, is a widely available and familiar method for monitoring opioid use in chronic pain patients. Urine drug testing can help track patient compliance and expose possible drug misuse and abuse. We sought to evaluate current attitudes and practices regarding the use of urine drug testing among chronic pain patients taking opioids. To the best of our knowledge, this is one of the first such attempts in the literature to examine and document the practice patterns of urine drug testing in this context. A total of 99 attendees at the American Congress of Pain Medicine were surveyed in 2008 about their urine testing practices for patients on opioid therapy. Surprisingly, more urine testing was motivated by a desire to detect undisclosed substances than to evaluate appropriate opioid use. Some respondents never urine-tested their opioid patients, and about two-thirds of respondents had no formal training in urine testing of patients on opioid therapy. The literature does not thoroughly address the role of urine drug testing in this patient population. Most respondents did random rather than scheduled testing; few had any urine testing protocol. The study found motivations for urine testing and testing practices varied widely, and urine testing, despite its clinical utility, is not used consistently.

Assessment of mass spectrometry-based pain management testing in clinical laboratories across North America.

BACKGROUND: Urine drug testing (UDT) is a useful tool in monitoring compliance to prescribed medication and can also help identify behaviors of drug misuse, abuse, and diversion. Mass spectrometry (MS)-based screening is recommended as the first-line of UDT for pain management patients; however, this testing comes with an inherent lack of standardization in methodologies and various analytical challenges. The objective of this study was to assess the current state of UDT for pain management in a cross-section of clinical laboratories in North America. MATERIALS AND METHODS: A total of 10 blinded urine samples were sent to 6 laboratories across the United States and Canada. Urine samples containing drugs and/or metabolites of interest were included to represent different clinical scenarios commonly seen in pain management settings. Assessment was based on the ability of the laboratories to correctly identify drugs and provide a meaningful interpretation of the findings (when offered by the performing laboratory). RESULTS: Across the laboratories involved in the study, 85% of tests correctly identified and appropriately reported the drugs present in the urine samples. Similarly, 84% of samples were considered to have an accurate interpretation included in the UDT report. Out of the total number of drugs included in the samples, 11% were not offered on every test menu. CONCLUSIONS: This study revealed the lack of standardization in pain management UDT performed in a limited cross-section of clinical laboratories across North America.

Determination of urinary prostaglandin E2 as a potential biomarker of ureteral stent associated inflammation.

Ureteral stents are the most widely used surgical implant in urology. However, they may cause adverse effects to patients, including pain, discomfort, and inflammation. In this work, the inflammatory effect of stent placement and the associated elevation of cyclooxygenase-2 (COX-2) expression were observed. Furthermore, a capillary electrophoresis mass spectrometry (CE-MS) based approach was subsequently developed to quantify urinary prostaglandin E2 (PGE2), a COX-2 metabolite known to contribute to inflammatory renal diseases, to further interrogate the role of this pathway. Urine samples were cleaned and preconcentrated by solid-phase extraction (SPE), and an on-line sample stacking method was used for the enrichment of analytes. The accuracy, precision, and specificity of this method were validated. Standard addition methods were performed to assess the reliability of using deuterated internal standards (IS) in compensating the remaining matrix effect after SPE as well as the detector fluctuation. Through the analysis of 32 pig urine samples, a statistically significant increase of PGE2 was observed in the stented group compared to the unstented (P = 0.01) and the recovered (P = 0.004) groups. This work determined that stent placement may contribute to COX-2-dependent inflammation and developed a reliable CE-MS based methodology to quantify PGE2 in stented individuals that may further understand the biology of stent-associated inflammation and inform urologic patient management.

Urinary cysteinyl leukotriene E(4) is associated with increased risk for pain and acute chest syndrome in adults with sickle cell disease.

Leukotriene E(4) (LTE(4)) levels are associated with rate of pain episodes in children with sickle cell disease (SCD). Because complications of SCD manifest differently in adults than children, we examined a cohort of adults with SCD to determine the relationship between baseline LTE(4) and SCD-related morbidity. Baseline LTE(4) levels were associated with increased rates of pain and acute chest syndrome (ACS) episodes, when those with LTE(4) values in the highest tertile were compared with those in the lowest tertile (pain: risk ratio 7.1, 95% CI 1.8-27.5, P = 0.005; ACS: risk ratio 12.2, 95% CI 2.1-69.8, P = 0.005).

Urinary cysteinyl leukotriene E4 significantly increases during pain in children and adults with sickle cell disease.

Baseline level of the cysteinyl leukotriene (CysLT), leukotriene E4 (LTE4), is associated with an increased pain rate in children and adults with sickle cell disease (SCD). To provide additional evidence for a role of CysLTs in the pathogenesis of vaso-occlusion, we tested the hypothesis that LTE4 levels will increase within an individual during painful episodes compared to baseline. In a cohort of 19 children and adults with SCD, median LTE4 levels increased from 82.36 pg/mg creatinine at baseline to 162.81 pg/mg creatinine during a painful episode (P < 0.001). These data further support a contribution of CysLTs to the process of vaso-occlusion.

LC-MS/MS extends the range of drug analysis in pain patients.

The current study addresses the distribution of low concentrations of excreted drugs in the pain patient population in an effort to establish a more rational set of cutoffs for this cohort. To wit, 19 analytes in approximately 8000 urine specimens from pain patients were measured using liquid chromatography tandem mass spectroscopy (LC-MS/MS) methodology. The lower limits of quantitation for the LC-MS/MS were set as the nominal cutoffs for the determination of positive and negative results. The measured concentrations were compared with the Substance Abuse & Mental Health Services Administration (SAMHSA) nominal immunoassay cutoffs, and a subset of "missed samples" was identified for each of the 19 analytes. This "missed samples" subset contained all samples that measured above the LC MS/MS cutoff for a given analyte but below the SAMHSA immunoassay cutoff. The number of "missed samples" divided by the total number of samples measured positive by the LC-MS/MS method defines the percentage of this population that would have been found falsely negative if a prescreen by immunoassay using SAMHSA cutoffs had been conducted. For example, 69% of the specimens that were positive for hydromorphone by LC-MS/MS would have been falsely scored as negative by immunoassay.

Anomalous observations of codeine in patients on morphine.

Urine drug monitoring is used by physicians treating chronic pain patients with opioid therapy. Patients are tested in part to insure that they are not taking other drugs. Therefore, the finding of codeine in a patient who is only prescribed morphine has clinical implications. Morphine preparations are known to have small amounts of codeine as an impurity estimated to be about 0.04%. In a population of 535 pain patients prescribed morphine, Kadian, MS Contin, and/or Avinza, the investigators observed 24 samples that contained codeine >20 ng/mL. Fifteen of the 24 contained codeine >20 and <50 ng/mL. Of the 9 samples that were >50 ng/mL, 7 had high levels of codeine (indicating codeine use), 1 was from a patient who had a prescription for codeine, and 1 was also positive for 6-acetylmorphine, indicating heroin use. A control group of 680 patients taking oxycodone was negative for codeine. The finding of codeine was ascribed to the manufacturing process of the morphine medications. Clinicians and laboratories testing urine for drugs should be aware of this possibility.

6-Acetylmorphine detected in the absence of morphine in pain management patients.

Liquid chromatography tandem mass spectrometry was used to identify and confirm the presence of 6-acetylmorphine and morphine in 22,361 urines of pain management patients. Thirty urines tested positive for 6-acetylmorphine above a cutoff of 10 ng/mL. Twenty-three percent of the patients with urinary concentrations of 6-acetylmorphine above 10 ng/mL had urinary morphine concentrations below 300 ng/mL.

Change in urinary markers of osteoclast activity following palliative radiotherapy for bone metastases.

AIMS: To examine the effect of radiotherapy for bone metastases on urinary markers of osteoclast activity. MATERIALS AND METHODS: Patients with radiological evidence of bone metastases planned for palliative radiotherapy were eligible for the study. A urine specimen was collected before and 1 month after radiotherapy to assess levels of calcium, creatinine, magnesium, phosphate, N-telopeptide and pyridinoline. The Brief Pain Inventory was completed in person at baseline and by telephone follow-up at 1 month after radiotherapy. Patients were classified as responders (complete or partial pain response) or non-responders (stable or progressive pain) to radiotherapy based on the International Bone Metastases Consensus Criteria for end point measurements. Absolute values of urine markers were compared between responders and non-responders, or between responders and patients with progression. RESULTS: Our study population consisted of 74 men and 51 women. A single 8 Gy or 20 Gy in five daily fractions were commonly employed. At the 1 month follow-up, all Brief Pain Inventory functional interference scores showed a highly significant decrease from baseline (P<0.01). From our study population, 58 (64%) were classified as responders and 57 (46%) as non-responders to radiotherapy. We compared the urinary markers between the responders and the non-responders. There were no statistically significant differences between the two groups either in terms of baseline markers or in terms of month 1 follow-up markers. There was no significant change from baseline to the 1 month follow-up in responders or in non-responders to radiotherapy. CONCLUSION: Baseline levels of urinary markers could not predict which patient would benefit from palliative radiotherapy.