Rabia S. Atayee

Novel opioid antagonists for opioid-induced bowel dysfunction.

Introduction: Adverse effects frequently limit the therapeutic benefits of opioid analgesics. Gastrointestinal adverse effects are common, burdensome, and can compromise the quality of life. It is estimated that up to 81% of patients still report constipation despite regular use of laxatives. Thus, the development of opioid antagonists that selectively target receptors in the gut without affecting central analgesia has provided new perspectives on the treatment of opioid-induced gastrointestinal adverse effects. Areas covered: In this paper, we review the pathophysiology, prevalence, and burden of opioid-induced bowel dysfunction (OBD). In addition, this study aims to provide a better understanding of the mechanism of action and reviews the efficacy, safety and the latest research on novel opioid antagonists for OBD. Expert opinion: Two strategies effectively relieve OBD without interfering with centrally mediated analgesia: the administration of opioid antagonists with limited systemic absorption and peripherally acting mu-opioid receptor antagonists (PAMORA) that selectively target mu-receptors in the gastrointestinal tract. Methylnaltrexone and alvimopan are two recently marketed PAMORA and provide a new mechanism-based approach for the treatment of opioid-induced gastrointestinal dysfunction. However, its use in clinical practice is limited by various reasons such as its relatively low response rates and higher costs. Nevertheless, at least four new oral PAMORA (NKTR-118, TD-1211, ADL-7445, and ADL-5945) are under clinical development, further expanding the possibilities for a new paradigm for OBD management.

Development of an Ambulatory Palliative Care Pharmacist Practice

PURPOSE The roles of a pharmacist in hospice and inpatient palliative care settings have been described. However, no reports of a palliative care pharmacist in an ambulatory care setting have been published. Our objective was to establish a model for incorporating an outpatient clinical pharmacist as part of a multidisciplinary palliative care team. METHODS A palliative care pharmacist based out of a retail pharmacy was incorporated as part of a consultative ambulatory palliative care service (known as the Doris A. Howell Service) at the University of California, San Diego Moores Cancer Center. The pharmacist completed all legal requirements to prescribe under a collaborative practice agreement in California (including National Provider Identifier [NPI] and US Drug Enforcement Agency [DEA] US Drug Enforcement Agency (DEA) registration). RESULTS From November 2006 through August 2007, the palliative care pharmacist consulted 29 new patients (the average age of patients was 49; range, 20-78 years) who had 114 clinic visits. The most common reason for referral to the palliative care pharmacist was for pain management (27/29; 93%). During the 114 patient clinic visits, 98% (112/114) of the palliative care pharmacist medication recommendations were accepted by the primary care oncologist. Physicians completed a satisfaction survey and reported that the top three useful activities of the Howell Service were: additional time spent with patients without physician present (90.9%), pain and symptom management (81.8%), and psychosocial support (72.7%). CONCLUSION This is the first report of a palliative care pharmacist in a retail-based ambulatory care setting. Initial results demonstrate the success of this pilot program.

Relationship between the Concentration of Hydrocodone and its Conversion to Hydromorphone in Chronic Pain Patients Using Urinary Excretion Data

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 (R(2) = 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 creatinine-corrected hydrocodone had a coefficient of determination of R(2) = 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.

Ketamine Mouthwash for Mucositis Pain

PURPOSE Our objective was to determine if an oral ketamine swish and expectorate was a safe and effective method to alleviate mucositis pain. METHODS A retrospective chart audit was preformed on eight patients who received ketamine mouthwash (20 mg/5 mL) for refractory mucositis pain. RESULTS All eight patients had mucositis pain refractory to a mucositis mixture (lidocaine, magnesium/aluminum hydroxide, and diphenhydramine) and opioids. An improvement in mucositis pain was seen in over half (5/8) of the patients. Four of eight patients had adverse effects that could have been associated with the ketamine mouthwash; all side effects were transient and subsided when the ketamine mouthwash was stopped. CONCLUSION Ketamine swish and expectorate may be a viable treatment option in refractory mucositis pain.

Observations on the Urine Metabolic Ratio of Oxymorphone to Oxycodone in Pain Patients

The object of this study was to evaluate the metabolism of oxycodone to oxymorphone in a pain patient population using a quantitative liquid chromatography-tandem mass spectrometry analysis of 32,656 urine specimens obtained from pain patients between March 2008 and Feb 2010. The observed excretion was modeled using logarithmic transformation and approximated a Gaussian distribution. Oxycodone excretion into urine had a geometric mean of 1.93 mg/g of creatinine and oxymorphone had a value of 0.41 mg/g of creatinine. Increasing concentrations of oxycodone correlated with a smaller proportion of oxymorphone excretion suggesting saturation of oxycodone metabolism. Urine samples containing oxycodone without oxymorphone allowed an estimation of the proportion of poor metabolizers (2.4 ± 2.1%) in the population. A similar analysis of samples containing oxymorphone without oxycodone gave an estimate of the proportion of ultra-rapid metabolizers (1.8 ± 1.1%) in the population. Samples with concentrations of oxycodone above 10 mg/g of creatinine showed a sub-population of subjects with metabolic ratios roughly 100-fold less than the linear predictive model in this study. This study describes typical ranges for oxycodone and oxymorphone in urine, and showed that it is possible to identify fast or slow metabolizers who may be at risk for adverse events.

Methylnaltrexone: a novel approach for the management of opioid-induced constipation in patients with advanced illness

In April 2008, the US FDA granted approval to methylnaltrexone (Relistor®), the first peripheral µ-opioid-receptor antagonist for the treatment of opioid-induced constipation in advanced-illness patients receiving palliative care and for whom other laxative therapies failed to achieve adequate results. Methylnaltrexone, a quaternary derivative of naltrexone, introduces a novel mechanism of action that selectively antagonizes the peripheral µ-receptors in the GI tract without effects on the CNS. In clinical trials, subcutaneous methylnaltrexone reversed opioid-induced constipation after the first dose in approximately 50–60% of the patients. In most of the cases, effective laxation occurred within 1 h. The therapeutic benefit was sustained in multiple-dose studies. Owing to the nature of the population studied, safety data are available for approximately 4 months of use. Although it is not the focus of this article, methylnaltrexone’s mechanism of action suggests it could be beneficial for other peripheral, opioid-induced adverse effects, such as opioid-related nausea, vomiting, urinary retention, pruritus or postoperative ileus.

Clinical Interpretation of Urine Drug Tests: What Clinicians Need to Know About Urine Drug Screens

&NA; Urine drug testing is frequently used in clinical, employment, educational, and legal settings and misinterpretation of test results can result in significant adverse consequences for the individual who is being tested. Advances in drug testing technology combined with a rise in the number of novel misused substances present challenges to clinicians to appropriately interpret urine drug test results. Authors searched PubMed and Google Scholar to identify published literature written in English between 1946 and 2016, using urine drug test, screen, false‐positive, false‐negative, abuse, and individual drugs of abuse as key words. Cited references were also used to identify the relevant literature. In this report, we review technical information related to detection methods of urine drug tests that are commonly used and provide an overview of false‐positive/false‐negative data for commonly misused substances in the following categories: cannabinoids, central nervous system (CNS) depressants, CNS stimulants, hallucinogens, designer drugs, and herbal drugs of abuse. We also present brief discussions of alcohol and tricyclic antidepressants as related to urine drug tests, for completeness. The goal of this review was to provide a useful tool for clinicians when interpreting urine drug test results and making appropriate clinical decisions on the basis of the information presented.

Clinical utility of naloxegol in the treatment of opioid-induced constipation

Opioids are a class of medications frequently used for the treatment of acute and chronic pain, exerting their desired effects at central opioid receptors. Agonism at peripherally located opioid receptors, however, leads to opioid-induced constipation (OIC), one of the most frequent and debilitating side effects of prolonged opioid use. Insufficient relief of OIC with lifestyle modification and traditional laxative treatments may lead to decreased compliance with opioid regimens and undertreated pain. Peripherally acting mu-opioid receptor antagonists (PAMORAs) offer the reversal of OIC without loss of central pain relief. Until recently, PAMORAs were restricted to subcutaneous route or to narrow patient populations. Naloxegol is the first orally dosed PAMORA indicated for the treatment of OIC in noncancer patients. Studies have suggested its efficacy in patients failing traditional constipation treatments; however, insufficient evidence exists to establish its role in primary prevention of OIC at this time.

Urinary Diazepam Metabolite Distribution in a Chronic Pain Population

Diazepam is often used as an adjuvant to pain therapy. Cytochrome P450 (CYP) 3A4 and 2C19 metabolize diazepam into the active metabolites: nordiazepam, temazepam and oxazepam. Owing to diazepams side-effect profile, mortality risk and potential for drug-drug interactions with CYP 3A4 and/or CYP 2C19 inhibitors, urine drug testing (UDT) could be a helpful monitoring tool. This was a retrospective data analysis that evaluated urine specimens from pain management practices for the distribution of diazepam metabolites with and without CYP 3A4 and 2C19 inhibitors. Intersubject nordiazepam, temazepam and oxazepam geometric mean fractions were 0.16, 0.34 and 0.47, respectively. Intrasubject geometric mean fractions were 0.157, 0.311 and 0.494, respectively. Sex, but not age or urinary pH, had an effect on metabolite fractions. Methadone significantly increased temazepam and oxazepam urinary fractions via CYP3A4 inhibition, whereas fluoxetine and esomeprazole increased nordiazepam fractions via CYP2C19 inhibition. Although more studies are needed, these results suggest the viability of UDT for increased monitoring for therapy and possible drug-drug interactions.

A Single-Center, Retrospective Analysis Evaluating the Utilization of the Opioid Risk Tool in Opioid-Treated Cancer Patients

ABSTRACT The Opioid Risk Tool (ORT) is a screening tool used to assess risk of opioid misuse by stratifying aberrant drug-seeking behaviors and/or identifying known risk factors for drug abuse. The objectives of this study were to risk stratify opioid misuse in a cancer pain population and determine the most common patient risk factors associated with misuse utilizing the ORT. This was a retrospective analysis conducted at an academic comprehensive cancer center. Patients were referred by an oncologist or hematologist to an outpatient palliative care clinic. One-hundred and fourteen patients with cancer (n = 107) or sickle cell disease (n = 7) were evaluated from July 2012 to July 2013. During the clinical interview, patients responded to a clinician administered ORT. Based on the ORT score, patients were stratified into low, moderate, or high risk for opioid misuse. Sample size included 57 men and 57 women. Sixty-five, 21, and 28 patients were deemed low, moderate, and high risk based on the ORT, respectively. The most common risk factors for opioid misuse were a history of depression (women = 32; men = 22) and family history of alcohol abuse (women = 26; men = 22). There was no difference between men and women in the prevalence of depression (P = .17) or family history of alcohol abuse (P = .57). The least common risk factor was a personal history of prescription drug abuse (n = 1) in women and history of preadolescent sexual abuse in men (n = 0). Twenty-five percent (n = 28) of the sample population were deemed high risk based on the ORT. Screening of cancer patients in the palliative care setting suggests that risk factors for opioid misuse exist. Stratifying patients based on a routine screening tool may help identify cancer patients at risk for aberrant drug behaviors.