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Hughes M.M.,University of California at San Diego | Atayee R.S.,University of California at San Diego | Best B.M.,University of California at San Diego | Pesce A.J.,Millennium Research Institute | Pesce A.J.,University of California at San Diego
Journal of Analytical Toxicology | Year: 2012

Morphine is one of several opioids used to treat chronic pain. Because of its high abuse potential, urine drug tests can confirm "consistency with prescribed medications." Hydromorphone is a recently described minor metabolite of morphine, but few data exist on the characteristics of this metabolic pathway or the relationship of morphine and hydromorphone between and within subjects. Part I of this retrospective study shows that formation of hydromorphone from morphine is concentration-dependent and possibly saturated at high concentrations of morphine. In addition, the percentage of ultra-rapid metabolizers and poor metabolizers can be determined using the lower asymptote of a sigmoidal mathematical fit and are estimated to be 0.63 and 4.0%, respectively. Expected limits of morphine and hydromorphone (as a result of morphine metabolism) concentrations in the urine were established. Part II of this study used the metabolic ratio (hydromorphone-morphine) to determine the inter-patient and intra-patient variability in morphine metabolism to hydromorphone. Metabolic ratio values varied over a large range; 25-fold and 7-fold, respectively. The expected limits established in this study can assist in assessing the cause for possible variances in metabolism, such as drug interactions. The wide variability between and within subjects may explain unpredictable, adverse effects. © The Author [2012]. Published by Oxford University Press. All rights reserved. Source


Leimanis E.,University of California at San Diego | Best B.M.,University of California at San Diego | Atayee R.S.,University of California at San Diego | Pesce A.J.,Millennium Research Institute | Pesce A.J.,University of California at San Diego
Journal of Analytical Toxicology | Year: 2012

Methadone is used to treat moderate to severe pain in patients not responsive to non-narcotic analgesics and for maintenance treatment of opioid addiction. Methadone is primarily metabolized by N-demethylation to an inactive metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP) by CYP3A4 and CYP2B6. Establishing expected concentrations for metabolism of methadone to EDDP using urine excretion data may be useful for monitoring "medications" and toxicity. Urine specimens from chronic pain patients were collected during routine clinic visits. Methadone and EDDP were quantified by liquid chromatography-tandem mass spectrometry. Approximately 8,000 subjects who reported taking methadone had creatinine concentrations ≥ 20 mg/dL, and excreted concentrations of methadone and EDDP above ≥ 100 ng/mL were selected. The median methadone urine concentration was 3.03 mg/g cr. Ninety-five percent of the population had concentrations between 0.175 and 20.9 mg/g cr. EDDP was, on average, twice the methadone concentration. The wide variance in relationship of methadone to its metabolite was not concentration-dependent. Variability between subjects was larger than variability within subjects. As the urinary pH increased, the proportion of excreted EDDP increased, implying a preferred excretion of EDDP. © The Author [2012]. Published by Oxford University Press. All rights reserved. Source


Barakat N.H.,University of California at San Diego | Atayee R.S.,University of California at San Diego | Best B.M.,University of California at San Diego | Pesce A.J.,Millennium Research Institute | Pesce A.J.,University of California at San Diego
Journal of Analytical Toxicology | Year: 2012

Hydrocodone in combination with acetaminophen is commonly used to control moderate pain and is metabolized by cytochrome P4502D6 to form the active metabolite, hydromorphone. The purpose of this study was to determine the metabolic relationship and variability between hydrocodone and its conversion to hydromorphone using urinary excretion data from chronic pain patients. Liquid chromatography-tandem mass spectrometry was used to quantitate hydrocodone and hydromorphone concentrations in urine specimens. The first visits of 25,200 subjects who took hydrocodone and not hydromorphone and had measurable concentrations were included in this study. The geometric mean (95% confidence index) of hydrocodone and hydromorphone urine concentrations were 1.39 (1.37-1.41) mg per gram of creatinine and 0.224 (0.221-0.227) mg per gram of creatinine, respectively. The log of creatinine-corrected hydromorphone versus the log of creatinine-corrected hydrocodone showed a positive relationship (R2 = 0.20), with 60-fold variability between subjects. The plot of the log of the metabolic ratio ([hydromorphone] divided by [hydrocodone]) versus the log of creatininecorrected hydrocodone had a coefficient of determination of R2 = 0.42, with 125-fold variability between subjects. Ultra-rapid metabolizers represented 0.6% of the population, whereas 4% were poor metabolizers. Within-subject variability for the excretion of hydrocodone in urine was 23-fold, whereas between-subject variability was 134-fold. Hydrocodone and hydromorphone urine concentrations showed great variability within and between subjects. © The Author [2012]. Published by Oxford University Press. All rights reserved. Source


Peppin J.F.,Mallinckrodt Pharmaceuticals | Cheatle M.D.,University of Pennsylvania | Kirsh K.L.,Millennium Research Institute | Mccarberg B.H.,Neighborhood Healthcare
Pain Medicine (United States) | Year: 2015

Objective: More than 25% of the US population experiences chronic pain; yet few physicians specialize in the field of pain medicine. This article will review a theoretical model of care that stratifies treatment and patients by level and type of complexity and promotes communication between specialist and primary care providers. Discussion: The undertreatment of pain was recently brought to national attention to encourage both clinicians and patients to advocate for improved pain care. The specialty of pain medicine and models of care, challenges of managing pain in a primary care setting, and the reliance on an opioid-focused approach are reviewed. An evolved model of pain care based on the complexity of pain and emphasizing a dynamic collaboration between the primary care provider and the pain specialist is discussed. Conclusions: From the perspective of the busy clinician, the treatment of chronic pain can be overwhelming. The scarcity of trained pain practitioners and the burgeoning number of patients with chronic pain necessitate a new approach that values the complex nature of chronic pain and offers a practical blueprint to meet these challenges. Wiley Periodicals, Inc. Source


Objective: Evaluate aberrant drug-related behaviors in patients administering fentanyl buccal tablet or traditional short-acting opioids for breakthrough pain. Design: Twelve-week open-label extension. Setting: Forty-two US sites. Subjects: Opioid-tolerant patients with chronic pain who completed the previous randomized, double-blind, crossover portion of a study comparing fentanyl buccal tablet and immediate-release oxycodone for treatment of breakthrough pain. Methods: Patients were rerandomized to continue treatment with fentanyl buccal tablet or begin any traditional short-acting opioid. Assessments included Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) at baseline and Addiction Behaviors Checklist and Current Opioid Misuse Measure at baseline and final visit. Case report forms were reviewed retrospectively to identify aberrant drug-related behaviors. Results: One hundred thirty patients entered the open-label extension (fentanyl buccal tablet, N=65; traditional short-acting opioid, N=65). SOAPP-R scores were <18 (low risk of aberrant drug-related behavior) in 74% of patients; no significant differences in SOAPP-R scores were observed between treatment groups. At the final visit, ≤14% of patients in each treatment group had scores indicating potential aberrant drug-related behavior (Addiction Behaviors Checklist ≥3, Current Opioid Misuse Measure ≥9); no significant differences in scores were observed between treatment groups. Baseline SOAPP-R score ≥18 was not predictive of Addiction Behaviors Checklist ≥3 but was predictive of Current Opioid Misuse Measure ≥9. Aberrant behaviors were identified in 12 (18%) fentanyl buccal tablet patients and 13 (20%) traditional short-acting opioid patients. Conclusions: Incidence of aberrant drug-related behaviors was similar between patients taking fentanyl buccal tablet and traditional short-acting opioids over 12 weeks. © 2014 American Academy of Pain Medicine. Source

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