Association of polypharmacy and potential drug-drug interactions with adverse treatment outcomes in older adults with advanced cancer.

BACKGROUND: Polypharmacy is common in older adults who are starting cancer treatment and is associated with an increased risk of potentially inappropriate medications (PIMs) and potential drug-drug interactions (PDIs). The authors evaluated the association of medication measures with adverse outcomes in older adults with advanced cancer who were receiving systemic therapy. METHODS: This secondary analysis from GAP 70+ Trial (ClinicalTrials.gov identifier NCT02054741; principal investigator, Supriya G. Mohile) enrolled patients aged 70 years and older with advanced cancer who planned to start a new treatment regimen (n = 718). Polypharmacy was assessed before the initiation of treatment and was defined as the concurrent use of eight or more medications. PIMs were categorized using 2019 Beers Criteria and the Screening Tool of Older Persons' Prescriptions. PDIs were evaluated using Lexi-Interact Online. Study outcomes were assessed within 3 months of treatment and included: (1) the number of grade ≥2 and ≥3 toxicities according to the National Cancer Institute Common Toxicity Criteria, (2) treatment-related unplanned hospitalization, and (3) early treatment discontinuation. Multivariable regression models examined the association of medication measures with outcomes. RESULTS: The mean patient age was 77 years, and 57% had lung or gastrointestinal cancers. The median number of medications was five (range, 0-24 medications), 28% of patients received eight or more medications, 67% received one or more PIM, and 25% had one or more major PDI. The mean number of grade ≥2 toxicities in patients with polypharmacy was 9.8 versus 7.7 in those without polypharmacy (adjusted ß = 1.87; standard error, 0.71; p <.01). The mean number of grade ≥3 toxicities in patients with polypharmacy was 2.9 versus 2.2 in patients without polypharmacy (adjusted ß = 0.59; standard error, 0.29; p = .04). Patients with who had one or more major PDI had 59% higher odds of early treatment discontinuation (odds ratio, 1.59; 95% confidence interval, 1.03-2.46; p = .03). CONCLUSIONS: In a cohort of older adults with advanced cancer, polypharmacy and PDIs were associated with an increased risk of adverse treatment outcomes. Providing meaningful screening and interventional tools to optimize medication use may improve treatment-related outcomes in these patients.

Association of Polypharmacy and Potentially Inappropriate Medications With Physical Functional Impairments in Older Adults With Cancer.

BACKGROUND: Polypharmacy and potentially inappropriate medications (PIMs) are prevalent in older adults with cancer, but their associations with physical function are not often studied. This study examined the associations of polypharmacy and PIMs with physical function in older adults with cancer, and determined the optimal cutoff value for the number of medications most strongly associated with physical functional impairment. METHODS: This cross-sectional analysis used baseline data from a randomized study enrolling patients aged ≥70 years with advanced cancer starting a new systemic cancer treatment. We categorized PIM using 2015 American Geriatrics Society Beers Criteria. Three validated physical function measures were used to assess patient-reported impairments: activities of daily living (ADL) scale, instrumental activities of daily living (IADL) scale, and the Older Americans Resources and Services Physical Health (OARS PH) survey. Optimal cutoff value for number of medications was determined by the Youden index. Separate multivariate logistic regressions were then performed to examine associations of polypharmacy and PIMs with physical function measures. RESULTS: Among 439 patients (mean age, 76.9 years), the Youden index identified ≥8 medications as the optimal cutoff value for polypharmacy; 43% were taking ≥8 medications and 62% were taking ≥1 PIMs. On multivariate analysis, taking ≥8 medications was associated with impairment in ADL (adjusted odds ratio [aOR], 1.64; 95% CI, 1.01-2.58) and OARS PH (aOR, 1.73; 95% CI, 1.01-2.98). PIMs were associated with impairments in IADL (aOR, 1.72; 95% CI, 1.09-2.73) and OARS PH (aOR, 1.97; 95% CI, 1.15-3.37). A cutoff of 5 medications was not associated with any of the physical function measures. CONCLUSIONS: Physical function, an important component of outcomes for older adults with cancer, is cross-sectionally associated with polypharmacy (defined as ≥8 medications) and with PIMs. Future studies should evaluate the association of polypharmacy with functional outcomes in this population in a longitudinal fashion.

Associations of Polypharmacy and Inappropriate Medications with Adverse Outcomes in Older Adults with Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Polypharmacy (PP) and potentially inappropriate medications (PIM) are highly prevalent in older adults with cancer. This study systematically reviews the associations of PP and/or PIM with outcomes and, through a meta-analysis, obtains estimates of postoperative outcomes associated with PP in this population. MATERIALS AND METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Register of Clinical Trials using standardized terms for concepts of PP, PIM, and cancer. Eligible studies included cohort studies, cross-sectional studies, meta-analyses, and clinical trials which examined outcomes associated with PP and/or PIM and included older adults with cancer. A random effects model included studies in which definitions of PP were consistent to examine the association of PP with postoperative complications. RESULTS: Forty-seven articles met the inclusion criteria. PP was defined as five or more medications in 57% of the studies. Commonly examined outcomes included chemotherapy toxicities, postoperative complications, functional decline, hospitalization, and overall survival. PP was associated with chemotherapy toxicities (4/9 studies), falls (3/3 studies), functional decline (3/3 studies), and overall survival (2/11 studies). A meta-analysis of four studies indicated an association between PP (≥5 medications) and postoperative complications (overall odds ratio, 1.3; 95% confidence interval [1.3-2.8]). PIM was associated with adverse outcomes in 3 of 11 studies. CONCLUSION: PP is associated with postoperative complications, chemotherapy toxicities, and physical and functional decline. Only three studies showed an association between PIM and outcomes. However, because of inconsistent definitions, heterogeneous populations, and variable study designs, these associations should be further investigated in prospective studies. IMPLICATIONS FOR PRACTICE: Polypharmacy and potentially inappropriate medications (PIM) are prevalent in older adults with cancer. This systematic review summarizes the associations of polypharmacy and PIM with health outcomes in older patients with cancer. Polypharmacy and PIM have been associated with postoperative complications, frailty, falls, medication nonadherence, chemotherapy toxicity, and mortality. These findings emphasize the prognostic importance of careful medication review and identification of PIM by oncology teams. They also underscore the need to develop and test interventions to address polypharmacy and PIM in older patients with cancer, with the goal of improving outcomes in these patients.

A Review of the Food and Drug Administration Adverse Event Reporting System for Tramadol-Related Hypoglycemia.

Background: Hypoglycemia is a rare adverse effect of tramadol that is described in the medical literature and package insert. Objective: The purpose of this study was to review reports of tramadol and hypoglycemia in the Food and Drug Administration Adverse Event Reporting System (FAERS) database to determine a potential association. Methods: Disproportionality analysis with Bayesian correction was used to compare tramadol and hypoglycemia with other medications in FAERS. The results were considered significant if the fifth percentile of the Empirical Bayesian geometric mean distribution (EB05) >2. Logistic regression odds ratios was used to determine if age, diabetes medications, and renal insufficiency masked the disproportionality of hypoglycemia, with the fifth percentile of the logistic regression odds ratio (LR05) >2 indicating a potential signal. The Interaction Signal Score (INTSS) was computed to determine the influence of predisposing risk factors on the signal. Results: A total of 605 cases of tramadol-associated hypoglycemia were reported, but our results were not significant (EB05: 1.590). Tramadol-associated hypoglycemia was significant in patients who did not take diabetes medications (EB05: 2.256; LR05: 2.2104). Renal insufficiency was not found to increase the risk of tramadol-associated hypoglycemia (INTSS: 0.865). There was a significant signal for tramadol-associated hypoglycemia in patients aged 0 to 1 year (LR05: 3.0240) and 2 to 4 years (LR05: 2.6853). Conclusion and Relevance: Results of our analysis suggest a potential signal between hypoglycemia and tramadol use in patients not taking diabetes medications. Our results do not support a predisposition for tramadol-associated hypoglycemia in patients with renal insufficiency, increasing age, and/or diabetes as noted in the tramadol package insert.

Extended-release hydrocodone: the devil in disguise or just misunderstood?

Opioid abuse in the United States increased significantly over the past decade, leading to opioid-related deaths. Approval of Zohydro ER, a product that lacks an abuse-deterrent formulation, has provoked media controversy and aggressive legislative action from multiple stakeholders. Only the American Academy of Pain Management has released a position statement on this medication, and individual opinion varies. Additional single-entity extended-release hydrocodone formulations are in the pipeline, and Zohydro ER's limited clinical utility may make the controversy associated with its approval a moot point. As with other opioids, providers will need to assess individual patient risk versus benefit when prescribing Zohydro ER.

Development and validation of a performance-based palliative care assessment tool for student pharmacists.

INTRODUCTION: Integration of hospice and palliative care principles within pharmacy curricula is essential to fill the need of pharmacist training in this growing specialty. A formalized assessment tool to evaluate skill development does not exist for student pharmacists specific to palliative care. The objective of this study was to develop a valid and reliable, palliative care-focused, performance-based assessment tool for student pharmacists. METHODS: Eight academic palliative care (PC) pharmacists were recruited for the workgroup to perform domain development, validation, tool creation, and reliability testing for this performance-based assessment tool. Hospice and palliative care clinical pharmacist entrustable professional activities (EPAs) served as the framework. Content validity testing utilized content validity index and scale universal agreement (S-CVI/UA) to determine level of agreement for activities included in the tool. Student volunteers completed a standardized patient case and workgroup members served as raters during the reliability testing phase. Interrater reliability was measured through calculation of Fleiss Kappa scores for each activity. RESULTS: Out of 14 EPAs, nine were deemed "essential" to include in the tool. Thirty-four supporting activities for the nine essential EPAs were drafted. Two rounds of content validity testing were necessary to achieve S-CVI/UA of 0.9593. Consensus was reached from workgroup members for activities deemed necessary to include in the tool after questionnaire distribution utilizing a Fleiss Kappa cutoff >0.6. CONCLUSIONS: This validated tool will afford colleges and schools of pharmacy with PC curricula an opportunity to assess student achievement of PC-specific skills and evaluate curricular effectiveness.

Gabapentin-Induced Overflow Urinary Incontinence: A Case Report and Review of the Literature.

Gabapentin (GBP) is a structural analog of gamma-aminobutyric acid (GABA) that is commonly used in palliative care for symptom management indications including neuropathic pain syndromes, hiccups, cough, and anxiety. An uncommon adverse effect of GBP is urinary incontinence (UI). We report the case of a 61-year-old male with metastatic non-small cell lung cancer who developed probable overflow UI while receiving 1200 mg/day of GBP for chemotherapy-induced peripheral neuropathy. The patient self-tapered GBP to 600 mg/day which resolved the overflow UI, but resulted in poorly controlled bilateral foot pain. The palliative care physician rotated the patient to pregabalin 150 mg/day and his bilateral foot pain improved after his regimen was titrated to 200 mg/day. The patient did not experience overflow UI while taking pregabalin despite the similar pharmacology and comparable doses to GBP. We believe this is the first case report to describe subsequent achievement of pain control by substituting pregabalin without recurrence of UI. Healthcare professionals should consider GBP as a potential cause when evaluating patients presenting with new onset overflow UI.

A Systematic Review of the Evidence Behind Use of Reduced Doses of Acetaminophen in Chronic Liver Disease.

Acetaminophen is among the most commonly used nonopioid analgesics, but significant variation exists in its prescribing practices for cirrhosis patients. Our primary objective was to describe the quality of evidence supporting or refuting the use of acetaminophen in patients with hepatic dysfunction. A comprehensive literature review of PubMed, Cochrane Library, Web of Science, and International Pharmaceutical Abstracts using the search terms "acetaminophen," "paracetamol," "chronic liver disease," "cirrhosis," and "hepatic disease" for studies describing changes in acetaminophen metabolism in patients with hepatic dysfunction was conducted. Twelve studies and four abstracts were included. Ten studies and three abstracts were pharmacokinetic studies. Two studies and one abstract evaluated the association of acetaminophen use and decompensation in the cirrhotic patient. The level of certainty for dosing recommendations obtainable from reviewing the evidence is low due to a small number of studies meeting search criteria, small samples sizes, inadequate information regarding cirrhosis etiology and compensated versus uncompensated liver disease, and lack of information on patient centered health outcomes. High-quality trials are not available to support the use of decreased acetaminophen doses in compensated cirrhosis patients. Acetaminophen can be a safe analgesic in patients with compensated hepatic dysfunction after careful analysis of patient-specific factors.

Methadone and Corrected QT Prolongation in Pain and Palliative Care Patients: A Case-Control Study.

BACKGROUND: Methadone (ME) is commonly used in pain and palliative care (PPC) patients with refractory pain or intolerable opioid adverse effects (AEs). A unique ME AE is its corrected QT (QTc) interval prolongation risk, but most evidence exists in methadone maintenance therapy patients. OBJECTIVE: Our goal was to identify QTc interval prolongation risk factors in PPC patients receiving ME and other medications known to prolong the QTc interval and develop a risk stratification tool. DESIGN: We performed a case-control study of adult inpatients receiving ME for pain management. Settings/Subjects: Adult inpatients receiving ME with a QTc >470 msec (males) and >480 msec (females) were matched 1:2 according to age, history of QTc prolongation, and gender with ME patients who did not have a prolonged QTc interval. QTc prolongation risk factors were collected for both groups. Covariates were analyzed using conditional logistic regression. Classification and regression tree analysis was used to identify the ME dose associated with QTc prolongation. RESULTS: Predictors of QTc prolongation included congestive heart failure (CHF) (OR: 11.9; 95% CI: 3.7-38.2; p < 0.00), peptic ulcer disease (PUD) (odds ratio [OR]: 8.3; 95% confidence interval [95% CI]: 2.4-28.9; p < 0.00), hypokalemia (OR: 6.5; 95% CI: 1.5-28.2; p < 0.01), rheumatologic diseases (OR: 4.7; 95% CI: 1.6-13.9; p < 0.00), taking medications with a known torsades de pointes (TdP) risk (OR: 4.4; 95% CI: 1.8-10.7; p < 0.01), malignancy (OR: 3.3; 95% CI: 1.2-9.3; p < 0.03), hypocalcemia (OR: 2.1; 95% CI: 0.9-4.8; p < 0.07), and ME doses >45 mg per day (OR: 1.9; 95% CI: 0.8-4.8; p < 0.16). Mild liver disease was protective against QTc prolongation (OR: 0.05; 95% CI: 0.0-0.46; p < 0.01). CONCLUSIONS: Predictors of QTc prolongation in our multivariate conditional logistic regression model included CHF, PUD, hypokalemia, rheumatologic disorders, use of medications with a known TdP risk, malignancy, hypocalcemia, and ME doses >45 mg per day.

A Pilot Chemical and Physical Stability Study of Extemporaneously Compounded Levetiracetam Intravenous Solution.

Levetiracetam is a commonly used antiepileptic medication for tumor-related epilepsy. However, the 100 mL intravenous (IV) infusion volume can be burdensome to imminently dying hospice patients. A reduced infusion volume would improve patient tolerability. The purpose of this study was to evaluate the stability of 1000 mg/25 mL (40 mg/mL) levetiracetam IV solution in sodium chloride 0.9%. We prepared levetiracetam 40 mg/mL IV solution and added it to polyvinyl chloride (PVC) bags, polyolefin bags, and polypropylene syringes. Triplicate samples of each product were stored at refrigeration (2-8°C) and analyzed on days 0, 1, 4, 7, and 14. Samples were subjected to visual inspection, pH measurement, and stability-indicating high-performance liquid chromatography (HPLC) analysis. Over the 2-week storage period, there was no significant change in visual appearance or pH for any of the stability samples. The HPLC results confirmed that all stability samples retained 94.2-101.3% of initial drug concentration and no degradation products or leachable material from the packaging materials were observed. We conclude that levetiracetam 1000 mg/25 mL IV solution in sodium chloride 0.9% is physically and chemically stable for up to 14 days under refrigeration in polypropylene syringes, PVC bags, and polyolefin bags.

Formulation and stability of an extemporaneously compounded oral solution of chlorpromazine HCl.

Chlorpromazine is a phenothiazine antipsychotic which is often used in hospice and palliative care to treat hiccups, delirium, and nausea. With the discontinuation of the commercial oral solution concentrate, there is a need to prepare this product by extemporaneous compounding. This study was initiated to identify an easy-to-prepare formulation for the compounding pharmacist. A stability study was also conducted to select the proper storage conditions and establish the beyond-use date. Chlorpromazine HCl powder and the Ora-Sweet® syrup vehicle were used to prepare the 100 mg/mL solution. Once the feasibility was established, a batch of the solution was prepared and packaged in amber plastic prescription bottles for a stability study. These samples were stored at refrigeration (2-8°C) or room temperature (20-25°C) for up to 3 months. At each monthly time point, the samples were evaluated by visual inspection, pH measurement, and high performance liquid chromatography (HPLC). A separate forced stability study was conducted to confirm that the HPLC method was stability indicating. A clear and colorless solution of 100 mg/mL chlorpromazine HCl was obtained by dissolving the drug powder in Ora-Sweet® with moderate agitation. The stability study results indicated that this solution product remained unchanged in visual appearance or pH at both refrigeration and room temperature for up to 3 months. The HPLC results also confirmed that all stability samples retained 93.6-101.4% of initial drug concentration. Chlorpromazine HCl solution 100 mg/mL can be compounded extemporaneously by dissolving chlorpromazine HCl drug powder in Ora-Sweet®. The resulting product is stable for at least three months in amber plastic prescription bottles stored at either refrigeration or room temperature.

Morphine and hydromorphone-induced hyperalgesia in a hospice patient.

Opioids including morphine and hydromorphone are widely used for control of moderate to severe pain and dyspnea in hospice and palliative care patients. Accumulation of the active morphine-3-glucuronide (M3G) and hydromorphone-3-glucuronide (H3G) metabolites is one proposed mechanism for the development of neuroexcitatory effects including allodynia and opioid-induced hyperalgesia (OIH). We report the case of a 43-year-old female hospice patient with metastatic non-small cell lung cancer who initially developed allodynia following morphine administration and again following administration of hydromorphone. The allodynia resolved both times following the discontinuation of the opioid and rotation to a different opioid regimen. Potential opioid-induced neuroexcitatory treatment options include opioid rotation to an agent with inactive metabolites, use of adjuvant pain medications for opioid-sparing effects, management of undesired symptoms (e.g., myoclonus), or increasing opioid clearance with intravenous (IV) fluids. Although the incidence is not well defined in the literature, hospice and palliative care clinicians should suspect OIH in patients with allodynia and/or hyperalgesia, especially when repeated dose escalations do not improve analgesia or pain escalates following opioid dose titration.

Dose ratios between high dose oral morphine or equivalents and oral methadone.

BACKGROUND: Methadone is a commonly used opioid in hospice and palliative care for patients with refractory pain. Various methadone dose conversion methods utilize progressively higher morphine equivalent dose (MED) to methadone dose ratios to compensate for increased methadone potency with escalating opioid doses. OBJECTIVE: The purpose of this study was to determine the dose ratio between equianalgesic doses of high dose oral morphine (daily doses >1200 mg morphine or MED) and oral methadone. METHODS: This study was a retrospective chart review of 324 patients who received methadone at Strong Memorial Hospital or the associated outpatient clinic during a nine-month period in 2011. Ten patients met the study inclusion and exclusion criteria. A Wilcoxon signed-rank test was used to compare the pain scale scores. The Spearman correlation coefficient was used to assess level of correlation between morphine dose and methadone dose. RESULTS: Patients rotated to methadone from high opioid doses had a two-point improvement in median pain scale scores after conversion (p=0.039). However, there was no correlation identified for patients taking daily doses >1200 mg oral morphine or MED prior to methadone rotation (p=0.19). There were no reported methadone adverse effects during the study. CONCLUSIONS: No correlation was identified between high MED doses and methadone at dose stabilization after opioid rotation. A fixed maximum methadone dose of 30 mg/day produced clinically meaningful improvements in pain scores without adverse drug effects. Caution should be exercised before considering rotation to methadone doses higher than 30 mg/day in a patient receiving >1200 mg oral MED/day.

Pharmacist credentialing in pain management and palliative care.

A credential is documented evidence of a pharmacist's qualifications; while credentialing is the method used to acquire, confirm, determine, and document a pharmacist's qualifications to practice. Voluntary credentials are important in clinical pharmacy specialties to ensure proficiency in caring for patients with complex pharmacotherapy needs. This article discusses current and future pharmacy pain management and palliative care credentialing opportunities. Pharmacists wishing to pursue voluntary pain management and palliative care credentialing may elect to take a multidisciplinary pain credentialing exam offered by the American Society of Pain Educators (ASPE) or American Academy of Pain Management (AAPM) and/or complete an American Society of Health System Pharmacists (ASHP) Postgraduate Year 2 (PGY2) pain management and palliative care pharmacy residency. A palliative care credentialing exam is not currently available to pharmacists. Efforts are underway within the pharmacy profession to standardize the board certification process, design a pain and palliative certificate program, and create a specialty pain management and palliative care board certification examination.

Seizure management in a complex hospice patient.

Antiepileptic medication use in noncancer hospice/palliative care patients is not well defined. The authors report the case of a human immunodeficiency virus (HIV) patient under hospice care with increased seizure frequency. The patient is a 22-year-old female with advanced HIV disease complicated by tonic-clonic seizures, hypoalbuminemia, gastroesophageal reflux disease (GERD), and gastritis. During an admission to the hospice inpatient unit, she developed increasing seizure frequency while receiving oral phenytoin. After collaboration between the clinical pharmacist and the hospice treating physician, they simplified her medication regimen, discontinued the phenytoin, and initiated oral levetiracetam. After these adjustments to her medication regimen, the patient's seizure frequency decreased significantly. This case illustrates the challenges of anticonvulsant use in advanced disease, including drug-drug interactions, impaired pharmacokinetics parameters, and increased risk of adverse effects. The importance of continuously monitoring patients for adverse drug events and assessing patient specific factors to help guide medication selection are also highlighted.