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Importance: Improved survival in patients with advanced cancer has increased the need for better understanding of how to manage common symptoms that they may experience, such as breathlessness., Objective: To assess the benefits and harms associated with pharmacologic interventions for breathlessness in adults with advanced cancer., Data Sources: PubMed, Embase, CINAHL, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies published from database inception through May 31, 2020, using predefined eligibility criteria within a PICOTS (population, intervention, comparator, outcome, timing, setting) format., Study Selection: Randomized clinical trials (RCTs), non-RCTs, and observational studies with a comparison group that evaluated benefits and/or harms and cohort studies that reported harms were selected., Data Extraction and Synthesis: Two reviewers independently screened studies for eligibility, serially abstracted data, independently assessed risk of bias, and graded strength of evidence (SOE)., Main Outcomes and Measures: Benefits and harms of pharmacologic interventions were compared, focusing on breathlessness, anxiety, exercise capacity, and health-related quality of life. When possible, meta-analyses were conducted and standardized mean differences (SMDs) calculated., Results: In this systematic review and meta-analysis, a total of 7729 unique citations were identified, of which 19 studies (17 RCTs and 2 retrospective studies) that included a total of 1424 patients assessed the benefits of medications for management of breathlessness in advanced cancer or reported harms. The most commonly reported type of cancer was lung cancer. Opioids were not associated with more effectiveness than placebo for improving breathlessness (SMD, -0.14; 95% CI, -0.47 to 0.18) or exercise capacity ( SMD, 0.06; 95% CI, -0.43 to 0.55) (SOE, moderate); most studies examined exertional breathlessness. Specific dose and/or route of administration of opioids did not differ in effectiveness for breathlessness (SMD, 0.15; 95% CI, -0.22 to 0.52) (SOE, low). Anxiolytics were not associated with more effectiveness than placebo for breathlessness or anxiety (reported mean between-group difference, -0.52; 95% CI, -1.045 to 0.005) (SOE, low). Evidence for other pharmacologic interventions was limited. Pharmacologic interventions demonstrated some harms compared with usual care, but dropout attributable to adverse events was minimal in these short-term studies (range 3.2%-16%)., Conclusions and Relevance: Evidence did not support the association of opioids or other pharmacologic interventions with improved breathlessness. Given that studies had many limitations, pharmacologic interventions should be considered in selected patients but need to be considered in the context of potential harms and evidence of an association of nonpharmacologic interventions with improved breathlessness.

Purpose: Concerns around chronic opioid use (COU), misuse, and harms have led to increased scrutiny of opioid prescribing in oncology. There is lack of research examining patient-level factors associated with COU. Our aim was to examine patient-level factors associated with COU in newly diagnosed cancer patients., Methods: Population-based retrospective cohort study using administrative health data of patients in Alberta, Canada, diagnosed between February 2016 and October 2017. Adult cancer patients who completed a symptom survey within ± 60 days of diagnosis were included. Patients were divided into two groups: COU (defined as continuous opioid prescriptions for at least 90 days post-diagnosis) and non-chronic opioid use (NCOU). Logistic regression was used to evaluate factors associated with COU., Results: We included 694 patients (mean age 65 years; 51% female). Most had breast (20%), colorectal (13%), and lung (33%) cancers. Of the 14% with COU, 79% were opioid naïve at diagnosis. Those in the COU group were more often diagnosed with advanced cancer (66% versus 40%), had lung cancer (47%), and were opioid tolerant (> 90 days of continuous opioids within one-year pre-diagnosis). A total of 64% of COU versus 27% of NCOU had moderate to severe pain at diagnosis (p < 0.001). Irrespective of treatment type or stage, those with moderate to severe pain, were opioid tolerant at diagnosis, or had multiple prescribers were at greater risk for COU., Conclusions: Specific patient groups were at increased risk of COU and should be the focus of adaptive prescribing approaches to ensure that opioid use is appropriate.

Purpose: The purpose of this study was to evaluate patient-related attitudinal barriers and identify associated factors in Chinese cancer inpatients receiving opioids and to explore relationships between patient-related attitudinal barriers, analgesic adherence and pain relief., Methods: A cross-sectional study was conducted. A total of 146 participants completed face-to-face surveys, including information about demographics, the Barriers Questionnaire-Chinese (BQ-C), analgesic adherence, average pain and breakthrough pain in the past 24 h. The Mann-Whitney U test and Kruskal-Wallis test were performed to test the differences in the attitudinal barrier scores between the adherence and nonadherence groups, the complete and incomplete pain relief groups and the groups based on demographics., Results: The majority of participants in this study were men (67.8%), over half of all participants were less than 60 years old, gastrointestinal cancer (47.3%) was the most common diagnosis and 59 (40.4%) acquired comprehensive pain education from the last discharge guidance procedure. The total BQ-C mean (SD) score was 1.61 ± 0.94. A total of 87 (59.6%) patients with cancer pain were completely relieved. Most of the patients (73.3%) completely took analgesics by orders. There was no significant difference in the total BQ-C score between the adherence group and the nonadherence group (P > 0.05), but the difference was significant between the complete pain relief group and the incomplete pain relief group (P < 0.05)., Conclusion: The findings of this study support unsatisfactory pain management and moderate analgesic adherence for Chinese inpatients. It is suggested that patient-related attitudinal barriers do not play an undermining role in pain management by negatively affecting patients' analgesic adherence. Conversely, patients' beliefs are more likely to be shaped by under treatment rather than as a cause.

Objective: To explore the clinical therapeutic effect of acupuncture combined with opioid drugs on moderate and severe cancer pain., Methods: A total of 60 patients with cancer were randomized into an observation group and a control group, 30 cases in each group. Oxycodonehydrochloride prolonged-release tablet was taken orally in the control group. On the basis of the control group, acupuncture was applied at Hegu (LI 4), Neiguan (PC 6), Zusanli (ST 36), Sanyinjiao (SP 6), etc. Corresponding back- shu points, xi -cleft points and ashi points were selected additionally according to primary viscera and pain sites in the observation group. The treatment was given once a day for 2 weeks. Symptomatic and supportive treatment were implanted, and no other antalgic measures were given during the trial. The daily dosage of opioid drug and the adverse reactions were recorded in both groups. Karnofsky performance status (KPS) and quality of life (QOL) scale scores were compared before and after treatment. Numerical rating scale (NRS) score was calculated to evaluate the clinical therapeutic effect., Results: Compared before treatment, the daily dosage of opioid drugs after treatment was obviously reduced in the observation group ( P <0.01), and was obviously increased in the control group ( P <0.05). The dosage of opioid drugs after treatment in the observation group was much less than the control group ( P <0.01). After treatment, the KPS and QOL scores were increased in both groups ( P <0.01), and the scores in the observation group were superior to the control group ( P <0.01, P <0.05). The analgesic effective rate was 90.0% (27/30) in the observation group, which was superior to 76.7% (23/30) in the control group ( P <0.05). The adverse reactions rate in the observation group was lower than the control group ( P <0.01)., Conclusion: Acupuncture combined with opioid drugs can effectively relieve the cancer pain, improve the performance status and quality of life in cancer patients, reduce the dosage of opioid drugs and adverse reactions rate.

Purpose of Review: This paper seeks to highlight GI motility disorders that are frequently present in patients with a malignancy. GI dysmotility can occur due to the cancer itself or as a consequence of medical and surgical treatments. Often, symptoms are nonspecific and the diagnosis requires a high index of suspicion. The goal of the paper is to review the common motility problems seen in patients with cancer, their clinical manifestations, and options for management., Recent Findings: Studies show that newer endoscopy techniques such as endoscopic mucosal dissection can cause esophageal dysmotility. Opioid-induced constipation is frequently encountered in patients with cancer. Motility disorders in cancer patient can lead to clinical morbidity, poor quality of life, and malnutrition. Newer diagnostic tests and medical and surgical treatments may be helpful in improving the diagnosis and management of these disorders.

Background: Patients with cancer receiving pregabalin potentially have a high incidence of central nervous system (CNS) symptoms. The purpose of this study was to explore clinical factors influencing the incidence of CNS symptoms, including plasma pregabalin exposure, cancer cachexia, and opioid analgesic cotreatment., Methods: Sixty-eight patients with cancer receiving twice-daily pregabalin were enrolled. Plasma concentrations of pregabalin, clinical laboratory data, opioid analgesic cotreatment, and the Glasgow Prognostic Score, which is an inflammation-based cachexia score, were considered as clinical factors. The incidence of CNS symptoms was collected from the patients' medical records. The predose plasma concentrations of pregabalin at steady state were determined by ultra-high-performance liquid chromatography., Results: The steady-state trough plasma pregabalin concentrations showed a large variability with an interquartile range of 0.43-1.2 mg/L per mg/kg and were negatively correlated with an estimated glomerular filtration rate (eGFR). C-reactive protein (standardized partial regression coefficient, β = 0.31) and opioid analgesic cotreatment (β = 0.24) were also identified in addition to eGFR (β = -0.60) in the multiple regression analysis. The incidence of CNS symptoms was significantly increased with opioid analgesic cotreatment and a higher Glasgow Prognostic Score but not with the absolute value of plasma pregabalin concentrations, eGFR, or other clinical laboratory data., Conclusions: In patients with cancer, steady-state trough plasma pregabalin concentrations were altered with renal function, systemic inflammation, and opioid analgesic cotreatment. However, a higher incidence of CNS symptoms observed in patients with cancer on pregabalin was more related to cachexia and opioid analgesic cotreatment than to altered pregabalin concentrations.

Objective: Sleep is often disturbed in patients with advanced cancer. There is limited knowledge about sleep in patients with cancer treated with strong opioids. This study examines sleep quality in patients with advanced cancer who are treated with a WHO Step III opioid for pain., Methods: An international, multicentre, cross-sectional study with 604 adult patients with cancer pain using WHO Step III opioids. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) global score (range; 0-21; score >5 indicates poor sleep). PSQI includes sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleep medications and daytime dysfunction. Pain and quality of life were assessed by Brief Pain Inventory and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core30., Results: The median age was 62 years, 42% were female, mean Karnofsky performance score (KPS) was 62.5 (±14.2) and mean oral daily morphine equivalent dose was 303 mg/24 hours (±543.8 mg). The mean PSQI global score was 8.8 (±4.2) (range 0-20). Seventy-eight per cent were poor sleepers. All PSQI components were affected, and 44% reported trouble sleeping caused by pain. In the multiple regression model, predictors of PSQI global scores were pain intensity, emotional function, constipation, financial difficulties and KPS (adjusted R 2 =0.21)., Conclusion: The majority (78%) of these patients with cancer treated with Step III opioids experienced poor sleep quality. Pain intensity, emotional function, constipation, financial difficulties and KPS predicted poor PSQI global scores. The clinical implication is that healthcare personnel should routinely assess and treat sleep disturbance in patients with advanced cancer disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Despite progress in treatments, cancer pain remains underestimated, poorly assessed and under-treated. Prescribing strong opioids, because of their specificities, requires precision in management considering their pharmacology but also a clear understanding of recommendations. Some clinicians highlight the risk of addiction, excessive sedation and respiratory depression and their need for information. Our objective in this review is to suggest some clinical guidance for the positioning and daily use of opioids within cancer pain management., Methods: Critical reflection based on literature analysis and clinical practice., Results: Strong opioids may be initiated as soon as pain diagnosis is defined. Factors to consider are pain aetiology, opioid pharmacokinetics and pharmacodynamics, genetic polymorphism, physiology (age, gender, weight and pregnancy), comorbidities (especially renal, hepatic, cardiovascular diseases), chronobiology, environmental factors, medication interference and treatment adherence. Achieving the best-balanced opioid treatment for background pain is complex, mainly due to the variable benefit/risk ratio between individuals and the experience of breakthrough cancer pain. Opioid initiation alongside a dynamic reassessment of pain should be fully integrated into the patient's management to optimise analgesia. The efficacy and safety of a strong opioid treatment need to be re-evaluated and adapted to individuals constantly as it varies over time., Conclusions: Cancer pain is multimorphic and permanently changing due to disease evolution, curative treatments and disruptive events (concomitant treatments, pain from associated disease, comorbidities and complications, modifications of the environment). Well-managed opioids are the cornerstone of a complex environment requiring multidisciplinary dynamic assessments integrated into the patient's care pathway.

Opioid-induced respiratory depression is a potentially life-threatening adverse drug event. The purpose of this study was to evaluate the incidence of respiratory depression using the Japanese Adverse Drug Event Report (JADER) Database to obtain data to promote proper use of opioids. The JADER database from April 2004 to March 2017 was obtained from the Pharmaceuticals and Medical Devices Agency. We calculated the reporting odds ratios (RORs) of suspected opioids (morphine, fentanyl, oxycodone, tapentadol, methadone, tramadol, pentazocine, buprenorphine, and codeine phosphate hydrate), analyzed the daily dose at first appearance and the time-to-onset profile, and assessed the hazard type using the Weibull shape parameter. ROR analysis detected adverse event signals for all opioids. Morphine showed a large ROR value with statistical significance in elderly (≥70 years old) patients. The median daily doses of oral morphine and oxycodone for inducing respiratory depression were comparably low (30 mg/d as oral morphine equivalent dose), while that of transdermal fentanyl was 120 mg/d (oral morphine equivalent dose). On time-to-onset analysis using the Weibull distribution, those opioids were classified as the early failure type. The median time-to-onset of oral morphine, oral oxycodone and transdermal fentanyl was 5.5, 11 and 12.5 d, respectively, and almost 50% of cases were reported within 30 d. Taken together, our results suggest that it is important to monitor patients carefully for at least the first one week to one month, even if opioids are administered at a relatively low dose, especially in elderly patients administered morphine.

Introduction and Objectives: According to World Health Organization recommendations, opioids prescription is a key aspect of improvement in cancer pain relief. However, studies on opioids prescription in France are scarce. This study aimed principally to investigate the impact of cancer on opioids prescription and then to identify factors associated with this prescription, focusing on patients& characteristics impact., Methods: We matched the following two cohorts: cancer survivors (N = 6,760) and individuals without cancer (N = 6,760). Using French health insurance databases, we compared the prevalence of prescribed opioids in 2009-2015 in people with and without cancer and we applied afterwards conditional Poisson regressions to estimate relative risks for monthly opioids prescription. For cancer survivors only (N = 3,055), multivariate negative binomial regressions were performed to identify factors associated with opioids prescription., Results: Cancer was associated with a higher analgesics prescription in the cancer population. While Step II and III opioids prescription decreased over time, the latter remained marginal and tended to stabilize. Older people were most adversely affected by underprescription of opioids, especially Step III opioids. Furthermore, although the matched case/control study suggested that men were prescribed opioids more often than women, multivariate analysis did not support this finding., Conclusion: The inconsistency between our findings and existing literature regarding both opioids prescription trends and postdiagnosis pain chronicity in cancer survivors over the medium term suggests possible changes in pain perception and the evolution of cancer pain management strategies. Further research should explore these hypotheses and investigate patient characteristics& effect in cancer pain management.

Opioids are highly effective for cancer pain but are associated with multiple adverse effects and risk of addiction. This article provides a synopsis on the management of various opioid-related adverse effects and strategies to minimize aberrant opioid use in patients who have cancer. Many adverse effects can be effectively managed. Some patients on chronic opioid therapy may demonstrate aberrant behaviors suggestive of opioid misuse or diversion. Through intensive education, longitudinal monitoring, early identification, and timely management, clinicians can optimize the risk to benefit ratio to support safe opioid use., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Context: In advanced cancer, abnormal sleep patterns may contribute to poor quality of life, but the impact of opioid-related sleep disorders has not been explored in detail in these patients., Objective: To document sleep and respiratory patterns in patients with cancer, receiving a range of opioids, determine factors that contribute to severity of central or obstructive apnea, and to what extent these contribute to sleep disturbance., Methods: Adults with advanced cancer admitted to a palliative care service underwent a sleep analysis by an unattended polysomnography. Total sleep time, apnea hypopnea index, central apnea index, obstructive apnea hypopnea index, arousal index, and oxygen desaturation were measured. Baseline assessment included body habitus, Mallampati score, comorbidity indices, concomitant medications, and the Berlin questionnaire. Epworth Sleepiness Scale, Stanford Sleepiness Scale, and Wu cancer fatigue scales were documented., Results: Twenty-eight patients were studied, including 25 receiving opioids. In the latter group, the apnea hypopnea index was mildly abnormal in six patients and severely abnormal in 10 patients. Central apnea index and obstructive apnea hypopnea index were abnormal in nine and 17 patients, respectively. There was no significant correlation between opioid dose and polysomnographic results., Conclusion: In patients with advanced cancer receiving opioid analgesia, there was a high prevalence of respiratory disturbance, both central and obstructive, and deranged sleep patterns. Addressing sleep-disordered breathing in cancer patients has the potential to improve daytime drowsiness and quality of life., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Opioid-free anaesthesia (OFA) is a technique where no intraoperative systemic, neuraxial or intracavitary opioid is administered with the anaesthetic. Opioid-free analgesia similarly avoids opioids in the perioperative period. There are many compelling reasons to avoid opioids in the surgical population. A number of case reports and, increasingly, prospective studies from all over the world support its benefits, especially in the morbidly obese population with or without sleep apnoea. A derivative technique is opioid sparing, where the same techniques are used but some opioid use is allowed. This chapter is a review of the current knowledge regarding opioid-free or low-dose opioid anaesthetic and analgesic techniques for the following special populations: obesity, sleep apnoea, chronic obstructive pulmonary disease, complex regional pain syndromes, acute/chronic opioid addiction and cancer surgery. Practical aspects include sympatholysis, analgesia and Minimum Alveolar Concentration (MAC) reduction with dexmedetomidine; analgesia with low-dose ketamine and co-anaesthesia; and sympatholysis with intravenous lignocaine. Non-opioid adjuvants such as NSAIDS, paracetamol, magnesium, local anaesthetic infiltration and high-dose steroids are added in the perioperative period to further achieve co-analgesia. Loco-regional anaesthesia and analgesia are also maximised. It remains to be seen whether OFA and early postoperative analgesia, which similarly avoids opioids, can prevent the development of hyperalgesia and persistent postoperative pain syndromes., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Context: Episodic dyspnea is one of the most common, debilitating, and difficult-to-treat symptoms., Objective: We conducted a pilot study to examine the effect of prophylactic fentanyl buccal tablet (FBT) on exercise-induced dyspnea., Methods: In this parallel, double-blind randomized placebo-controlled trial, opioid-tolerant patients were asked to complete a six-minute walk test (6MWT) at baseline and then a second 6MWT 30 minutes after a single dose of FBT (equivalent to 20-50% of their total opioid dose) or matching placebo. We compared dyspnea Numeric Rating Scale (NRS, 0-10, primary outcome), walk distance, vital signs, neurocognitive function, and adverse events between the two 6MWTs., Results: Among 22 patients enrolled, 20 (91%) completed the study. FBT was associated with a significant within-arm reduction in dyspnea NRS between 0 and six minutes (mean change -2.4, 95% CI -3.5, -1.3) and respiratory rate (mean change -2.6, 95% CI -4.7, -0.4). Placebo was also associated with a nonstatistically significant decrease in dyspnea (mean change -1.1). Between-arm comparison of dyspnea scores in the second 6MWT favored FBT, albeit not statistically significant (estimate -0.25, P = 0.068). Global impression revealed more patients in the FBT group than placebo group reporting their dyspnea was at least "somewhat better" in the second 6MWT (4 of 9 vs. 0 of 11, P = 0.03). The other secondary outcomes did not differ significantly between arms., Conclusions: This study supports that prophylactic FBT was associated with a reduction of exertional dyspnea and was well tolerated. Our findings support the need for larger trials to confirm the therapeutic potential of rapid-onset opioids., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Many chemotherapy treatments induce peripheral neuropathy (CIPN). These patients often experience neuropathic pain (NP) that reduces the quality of life. The aim of this prospective, open label study was to evaluate the efficacy and tolerability of tapentadol (TP) in patients affected by CIPN. CIPN were consecutively enrolled in a prospective open label study at the Neuro-Oncology Unit of the Regina Elena National Cancer Institute in Rome. During the titration phase, each patient initially received doses of TP 50 mg twice a day. All patients underwent pain intensity (NRS) and DN4. For evaluation of quality of life, patients underwent EORTC QLQ-C30 and EORTC QLQ-CIPN2 QLQ-CIPN20. We enrolled 31 patients, 19 were females with a median age of 60 years. After 3 months of treatment with TP, 22 patients completed the statistical package for social sciences (SPSS). Nineteen patients out of 22 showed a response to treatment (86%). We also observed that TP reduced the NRS and DN4 values from baseline to the last visit in a significant way (p < 0.001, respectively). Seven patients (22.5%) discontinued the TP therapy after the first week of occurrence of side effects. Furthermore, we observed that TP improved also the global health status measured by EORT QLQ-C30. TP is well tolerated and efficacy in the treatment of NP. The important reduction of neuropathic pain, the improvement in NRS and QoL scores after therapy with TP makes it a candidate in the management of patients suffering from neuropathic pain of CIPN also as a first line of therapy.

Cancer patients in pain require high doses of opioids and quickly become opioid-tolerant. Previous studies have shown that chronic cancer pain as well as high-dose opioid use lead to mu-opioid receptor downregulation. In this study we explore downregulation of the mu-opioid receptor gene (OPRM1), as a mechanism for opioid tolerance in the setting of opioid use for cancer pain. We demonstrate in a cohort of 84 cancer patients that high-dose opioid use correlates with OPRM1 hypermethylation in peripheral leukocytes of these patients. We then reverse-translate our clinical findings by creating a mouse cancer pain model; we create opioid tolerance in the mouse cancer model to mimic opioid tolerance in the cancer patients. Using this model we determine the functional significance of OPRM1 methylation on cancer pain and opioid tolerance. We focus on 2 main cells within the cancer microenvironment: the cancer cell and the neuron. We show that targeted re-expression of mu-opioid receptor on cancer cells inhibits mechanical and thermal hypersensitivity, and prevents opioid tolerance, in the mouse model. The resultant analgesia and protection against opioid tolerance are likely due to preservation of mu-opioid receptor expression on the cancer-associated neurons., Perspective: We demonstrate that epigenetic regulation of OPRM1 contributes to opioid tolerance in cancer patients, and that targeted gene therapy could treat cancer-induced nociception and opioid tolerance in a mouse cancer model., (Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Purpose This randomized, double-blind, multicenter study aimed to determine the dose of naldemedine, a peripherally-acting μ-opioid receptor antagonist, for future trials by comparing the efficacy and safety of three doses of naldemedine versus placebo in patients with cancer and opioid-induced constipation. Methods Patients ≥ 18 years old with cancer, an Eastern Cooperative Oncology Group performance status ≤ 2, who had been receiving a stable regimen of opioid analgesics for ≥ 2 weeks, had at least one constipation symptom despite laxative use, and no more than five spontaneous bowel movements (SBMs) during the past 14 days, were randomly assigned (1:1:1:1) to oral, once-daily naldemedine 0.1, 0.2, or 0.4 mg, or placebo, for 14 days. The primary end point was change in SBM frequency per week from baseline during the treatment period. Secondary end points included SBM responder rates, change from baseline in the frequency of SBM without straining, and complete SBM. Safety was also assessed. Results Of 227 patients who were randomly assigned, 225 were assessed for efficacy (naldemedine 0.1 mg, n = 55; 0.2 mg, n = 58; 0.4 mg, n = 56; placebo, n = 56) and 226 for safety. Change in SBM frequency (primary end point) was higher with all naldemedine doses versus placebo ( P < .05 for all comparisons), as were SBM responder rates and change in complete SBM frequency. Change in SBM frequency without straining was significantly improved with naldemedine 0.2 and 0.4 (but not 0.1) mg versus placebo (at least P < .05). Treatment-emergent adverse events were more common with naldemedine (0.1 mg: 66.1%; 0.2 mg: 67.2%; 0.4 mg: 78.6%) than placebo (51.8%); the most common treatment-emergent adverse event was diarrhea. Conclusion Fourteen-day treatment with naldemedine significantly improved opioid-induced constipation in patients with cancer and was generally well tolerated. Naldemedine 0.2 mg was selected for phase III studies.

Purpose Fentanyl sublingual tablets (FST) are a potentially useful alternative to parenteral opioids such as subcutaneous morphine (SCM) to treat severe cancer pain episodes. No direct comparison between FST and SCM is available. The aim of this study was to test noninferiority of FST versus SCM during the first 30 min postadministration. Methods Patients receiving stable opioid therapy and experiencing a severe pain episode were randomly assigned to either 100 µg FST or 5 mg SCM in a double-blind, double-dummy trial. Average pain intensity (PI) assessed on a 0 to 10 numerical rating scale at 10, 20, and 30 min postadministration was the main end point. Analysis of covariance, adjusted by baseline PI, was the main analysis. The noninferiority margin (NIm) for the between-group difference was set at -0.6, that is, equal to one third of the minimum clinically important PI difference of two points. Results A total of 114 patients were randomly assigned to either FST (n = 58) or SCM (n = 56). One patient (in the FST group) withdrew consent before drug administration and was excluded from analysis. Baseline mean PIs were 7.5 in both groups; mean average PIs assessed at 10, 20, and 30 min postadministration were 5.0 and 4.5 for FST and SCM, respectively, with the 95% CI of the between-group difference including the NIm (-0.49; 95% CI, -1.10 to 0.09). Patients taking FST received a second drug dose after 30 min more frequently than did patients taking SCM (51% v 37%, respectively; risk difference, -13%; 95% CI, -30% to 3%). Both treatments were well tolerated, with average follow-up adverse event scores below the response of "A Little." Ninety-three percent of patients preferred the sublingual administration. Conclusion This trial did not show noninferiority of FST versus SCM within the chosen NIm. Both treatments were safe, and patients preferred the sublingual route of administration. FST provides analgesia with modest to moderate increased risk of lower efficacy compared with SCM.

Purpose: Long-term cancer survivors develop special health issues and specific needs. Chronic pain, whether the consequence of their cancer or as a side effect of treatment, is one of their most prevalent concerns., Methods: We conducted a review of the English-language literature on long-term cancer survivorship and chronic opioid therapy, with the objective of determining the efficacy, safety and tolerability in this group of patients. Practical management recommendations are made on the basis of this review., Results: Pain syndromes encountered in the long-term cancer survivors are diverse. Opioid receptor pathways possess complex and pleiotropic functions and continuous over-activation may lead to de novo endocrinopathies, immunosuppression, neurocognitive impairment, or cell cycle disturbances with potential clinical connotations. However, there are insufficient data to support evidence-based decision making with respect to patient selection, doses, administration, monitoring and follow-up. Data about long-term treatment effectiveness and safety are limited and often aggravated by the overlapping of several diseases prevalent among long-term cancer survivors, as well as chronic opiate-induced toxicity., Conclusions: Chronic opioid therapy is frequent in long-term cancer survivors, and may negatively affect the immune system, and produce health problems such as endocrinopathies, osteoporosis, neurological or cardiopulmonary effects, alterations of cell cycle kinetics, abuse and addiction. This review highlights the need for specialized teams to treat chronic pain in long-term cancer survivors from an integrative perspective.

Pain remains common in the setting of malignancy, occurring as a consequence of cancer and its treatment. Several high-quality studies confirm that more than 50% of all patients with cancer experience moderate to severe pain. The prevalence of pain in cancer survivors is estimated to be 40%, while close to two-thirds of those with advanced disease live with pain. Progress has occurred in the management of cancer pain, yet undertreatment persists. Additionally, new challenges are threatening these advances. These challenges are numerous and include educational deficits, time restraints, and limited access to all types of care. New challenges to access are occurring as a result of interventions designed to combat the prescription drug abuse epidemic, with fewer clinicians willing to prescribe opioids, pharmacies reluctant to stock the medications, and payers placing strict limits on reimbursement. A related challenge is our evolving understanding of the risks of long-term adverse effects associated with opioids. And reflective of the opioid abuse epidemic affecting the general population, the potential for misuse or abuse exists in those with cancer. Guidelines have been developed to support oncologists when prescribing the long-term use of opioids for cancer survivors. The challenges surrounding the use of opioids, and the need for safe and effective alternative analgesics, are leading to intense interest in the potential benefits of cannabis for cancer-related pain. Oncologists are faced with questions regarding the types of cannabis available, differences between routes of administration, data concerning safety and efficacy, and legal and regulatory dynamics.

Context: Episodic breathlessness is common and debilitating in cancer patients., Objectives: In this pilot study, we examined the effect of prophylactic fentanyl pectin nasal spray (FPNS) on exercise-induced dyspnea, physiologic function, and adverse events., Methods: In this parallel, double-blind randomized placebo-controlled trial, opioid-tolerant patients performed three six-minute walk tests (6MWTs) to induce dyspnea. They were randomized to receive either FPNS (15%-25% of total daily opioid dose each time) or placebo 20 minutes before the second and third 6MWTs. We compared dyspnea Numeric Rating Scale (NRS, 0-10, primary outcome), walk distance, vital signs, neurocognitive function, and adverse events between the first and second 6MWTs (T2-T1) and between the first and third 6MWTs (T3-T1)., Results: Twenty-four patients enrolled, with 96% completion. FPNS was associated with significant within-arm reduction in dyspnea NRS at rest (T2-T1: -0.9 [95% CI -1.7, -0.1]; T3-T1: -1.3 [95% CI -2.0, -0.5]) and at the end of a 6MWT (T2-T1: -2.0 [95% CI -3.5, -0.6]; T3-T1: -2.3 [95% CI -4.0, -0.7]), and longer walk distance (T2-T1 +23.8 m [95% CI +1.3, +46.2 m]; T3-T1: +23.3 m [95% CI -1.7, +48.2]). In the placebo arm, we observed no significant change in walk distance nor dyspnea NRS at rest, but significant reduction in dyspnea NRS at six minutes (T2-T1: -1.7 [95% CI -3.3, -0.1]; T3-T1: -2.5 [95% CI -4.2, -0.9]). Vital signs, neurocognitive function, and adverse effects did not differ significantly., Conclusion: FPNS was safe, reduced dyspnea at rest, and increased walk distance in before-after comparison. The placebo effect was substantial, which needs to be factored in future study designs., Trial Registration: ClinicalTrials.govNCT01832402., Competing Interests: The authors have no conflicts of interest., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Episodic breathlessness (EB) or dyspnea is a common symptom with a very negative impact on the quality of life of patients with cancer and with non-oncological advanced diseases, mainly cardiorespiratory and neurological., Objective: The purpose of this non-systematic review is to ascertain the role played by opioids in the management of episodic breathlessness., Methods: A non-systematic literature review was done in the databases MEDLINE, COCHRANE, and DATABASE, and articles of greater scientific rigor, mainly reviews or prospective studies/randomized clinical trials published to date (August 2015), were selected. Terms used in the search included episodic breathlessness, acute breathlessness, episodic dyspnea, opioids, morphine, fentanyl, oxycodone, and breakthrough dyspnea., Conclusions: Although the pathophysiology and mechanism of action of opioids for management of breathlessness, and specifically EB, are not fully known, there is scientific evidence, and particularly great clinical evidence, of the benefit of this drug class for dyspnea management. It is important to differentiate hospitalized patients from outpatients because venous or subcutaneous access is easier in hospitalized patients, but use of transmucosal fentanyl, especially in faster formulations like intranasal application, opens up new possibilities to manage outpatients due to its fast onset of action. The main problem is the lack of data available and the multitude of unanswered questions about opioid type, administration route, safety, and dose titration.

Background: Research on the safety and efficacy of continuous lidocaine infusions (CLIs) for the treatment of pain in the pediatric setting is limited. This article describes a series of pediatric oncology patients who received lidocaine infusions for refractory, longstanding, cancer-related pain., Procedure: This is a retrospective review of patients who underwent lidocaine infusions to manage severe, opioid-refractory, cancer-related pain. Four patients ranging in age from 8 to 18 years were admitted to a pediatric hospital for their medical conditions and/or pain management. Structured chart review established demographic and diagnosis information, infusion rates, side effects, and efficacy of infusions in providing pain relief. Lidocaine bolus doses, infusion rates, serum concentrations, and subjective pain scores were analyzed., Results: Median pain scores prior to lidocaine infusions were 8/10, falling to 2/10 at the infusion termination (P < 0.003), and rising to 3/10 in the first 24 hr after lidocaine (P < 0.029 compared to preinfusion pain). The infusions were generally well tolerated, with few side effects noted. In most cases, the improvement in pain scores persisted beyond termination of the infusion., Conclusions: CLIs were a helpful adjuvant in the four cases presented and may be an effective therapy for a more diverse array of refractory cancer pain. The majority of patients experienced pain relief well beyond the metabolic elimination of the lidocaine, corroborating a modulation effect on pain windup. Additional research regarding infusion rates, serum concentrations, side effects, and outpatient follow-up in a larger group of patients will provide additional insight into the role and safety of this therapy in children., (© 2016 Wiley Periodicals, Inc.)

Context: Breathlessness is one of the most distressing symptoms experienced by patients with advanced cancer and noncancer diagnoses alike. Often, severity of breathlessness increases quickly, calling for rapid symptom control. Oral, buccal, and parenteral routes of provider-controlled drug administration have been described. It is unclear whether patient-controlled therapy (PCT) systems would be an additional treatment option., Objectives: To investigate whether intravenous opioid PCT can be an effective therapeutic method to reduce breathlessness in patients with advanced disease. Secondary aims were to study the feasibility and acceptance of opioid PCT in patients with refractory breathlessness., Methods: This was a pilot observational study with 18 inpatients with advanced disease and refractory breathlessness receiving opioid PCT. Breathlessness was measured on a self-reported numeric rating scale. Richmond Agitation Sedation Scale scores, Palliative Performance Scale scores, vital signs, and a self-developed patient satisfaction questionnaire were used for measuring secondary outcomes. Descriptive and interference analyses (Friedman test) and post hoc analyses (Wilcoxon tests and Bonferroni corrections) were performed., Results: Eighteen of 815 patients (advanced cancer; median age = 57.5 years [range 36-81]; 77.8% female) received breathlessness symptom control with opioid PCT; daily morphine equivalent dose at Day 1 was median = 20.3 mg (5.0-49.6 mg); Day 2: 13.0 mg (1.0-78.5 mg); Day 3: 16.0 mg (8.3-47.0 mg). Numeric rating scale of current breathlessness decreased (baseline: median = 5 [range 1-10]; Day 1: median = 4 [range 0-8], P < 0.01; Day 2: median = 4 [range 0-5], P < 0.01). Physiological parameters were stable over time. On Day 3, 12/12 patients confirmed that this mode of application provided relief of breathlessness., Conclusion: Opioid PCT is a feasible and acceptable therapeutic method to reduce refractory breathlessness in palliative care patients., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

The rationale for putting opioid antagonists with an agonist is to improve pain control, to reduce side effects, and/or to reduce abuse. The combination of prolonged release (PR) oxycodone and naloxone reduces constipation as demonstrated in multiple studies and has been designated a tamper-resistant opioid by the Food and Drug Administration. Bioequivalence of the combination product compared with PR oxycodone has not been established. Several of the pivotal studies provided suboptimal laxative support in the control arm of the randomized trials. Two noninferiority trials have demonstrated equivalent analgesia between PR oxycodone and the combination product at doses of less than 120 mg of oxycodone per day. There appears to be an analgesic ceiling above 80-120 mg of oxycodone per day. Safety monitoring during randomized trials was not been well described in published manuscripts. Benefits appear to be better for those with chronic noncancer pain compared with individuals with cancer when constipation was the primary outcome.

Objectives: The fear of using tramadol for pain control (tramadolophobia) by Egyptian patients with cancer is a frequent problem in our practice. This study was conducted to explore the prevalence of and the reasons behind tramadolophobia among Egyptian patients with cancer., Methods: A structured interview including open-ended and closed questions. The study included 178 adult patients with cancer from two cancer centers in Cairo and Sharkia, Egypt., Results: The source of information about tramadol was a non-healthcare-related source in 168 (94 percent) patients, mainly the media (50 percent). The believed uses of tramadol were abuse related in 94 (53 percent) patients, stimulant (physical, sexual, and to boost alertness) in 59 (33 percent), and analgesic in 55 (31 percent). Twenty-six (15 percent) patients gave history of tramadol use, largely (69 percent) as a stimulant. In case tramadol was prescribed for pain control, 90 (51 percent) patients refused to take it, 59 (33 percent) patients agreed to take it with concern about addiction, and only 29 (16 percent) patients agreed without concerns. Among those who refused taking tramadol for pain, the mentioned reason of refusal was addiction-related fears in 57 percent., Conclusions: The stigmatization and misconceptions about tramadol may have resulted in tramadolophobia among the majority of Egyptian patients with cancer. This further complicates the barriers to cancer pain control in Egypt. Being the only available World Health Organization step-II analgesic in Egypt, interventions to overcome tramadolophobia should be taken.

Context: Fentanyl products have shown superiority to oral opioids for the management of breakthrough cancer pain (BTcP). However, these studies did not use appropriate patient selection, and drugs have been compared by using different rationales., Objectives: The aim of this randomized, crossover, controlled study was to compare efficacy and safety of fentanyl buccal tablets (FBTs) and oral morphine (OM), given in doses proportional to opioid daily doses., Methods: Cancer patients with pain receiving ≥60 mg or more of oral morphine equivalents per day and presenting with ≤3 episodes of BTcP per day were included. In a randomized, crossover manner, patients received FBT or OM at doses proportional to the daily opioid regimen in four consecutive episodes of BTcP. Pain intensity was measured before (T0) and 15 (T15) and 30 minutes (T30), after study drugs., Results: In total, 263 episodes of BTcP were treated. A statistical difference in changes in pain intensity-decrease of ≥33% and ≥50%-between the two groups was observed at T15 and T30 (P < 0.0005). No severe adverse effects after study drug administration were observed., Conclusion: When used in doses proportional to the basal opioid regimen, FBT showed a clear superiority and was well tolerated when compared with OM during the first 30 minutes, which is the approximate target for a timely intervention required for a BTcP medication., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Measuring opioid concentrations in pain treatment is warranted in situations where optimal opioid analgesia is difficult to reach., Objectives: To assess the usefulness of oral fluid (OFL) as an alternative to plasma in opioid concentration monitoring in cancer patients on chronic opioid therapy., Methods: We collected OFL and plasma samples from 64 cancer patients on controlled-release (CR) oral morphine, CR oral oxycodone, or transdermal (TD) fentanyl for pain. Samples were obtained on up to five separate days., Results: A total of 213 OFL and plasma samples were evaluable. All patients had detectable amounts of the CR or TD opioid in both plasma and OFL samples. The plasma concentrations of oxycodone and fentanyl (determination coefficient R(2) = 0.628 and 0.700, respectively), but not morphine (R(2) = 0.292), were moderately well correlated to the daily opioid doses. In contrast to morphine and fentanyl (mean OFL/plasma ratio 2.0 and 3.0, respectively), the OFL oxycodone concentrations were significantly higher than the respective plasma concentrations (mean OFL/plasma ratio 14.9). An active transporter could explain the much higher OFL vs. plasma concentrations of oxycodone compared with morphine and fentanyl., Conclusion: OFL analysis is well suited for detecting the studied opioids. For morphine and fentanyl, an approximation of the plasma opioid concentrations is obtainable, whereas for oxycodone, the OFL/plasma concentration relationship is too variable for reliable approximation results., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Up to 44% of patients with cancer-related pain require opioid rotation (OR) because of inadequate analgesia or side effects. No consensus exists regarding the most efficacious method for rotation to methadone., Objectives: To define the available evidence regarding methods of rotation to methadone and to determine if sufficient evidence exists regarding the superiority of one method., Methods: A predefined search strategy, using Medical Subject Headings (MeSH) search terms and keywords combined using Boolean operators, was performed. Study selection was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. Data were extracted, quality of studies assessed, and narrative synthesis undertaken., Results: A total of 3214 potentially relevant studies were identified. Twenty-five studies were included: 15 retrospective and 10 prospective (n = 1229). One trial compared three-day switch (3DS) and rapid conversion (RC) methods; two, 3DS; 10, RC; nine, ad libitum (AL). Success rates were as follows: 3DS-93%, RC-71.7%, and AL-92.8%. The single clinical trial and retrospective studies demonstrated poorer analgesia and an excess of adverse events (AEs) in the RC group (five dropouts because of AEs) compared with the 3DS group (no severe AEs). Time to stable analgesia was as follows: RC <4.3 days and AL <6 days., Conclusion: Evidence identified was mainly from uncontrolled observational studies, making causality difficult to establish. Studies were heterogeneous in methodology and outcome measures. There was a trend toward excess AEs using the RC method, in comparison to the AL and 3DS methods. The methodological quality of the AL studies was low. A direct comparison of AL and 3DS methods would be informative., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Patient controlled anesthesia (PCA) is increasingly used to manage pain in pediatric cancer patients and is important in the treatment of escalating pain at the end of life. The description of the use of opioid PCA in this population has been limited., Procedure: This retrospective chart review of the last 2 weeks of life addressed the following objectives: (1) to describe the patient population treated with opioid PCA; (2) to describe the morphine-equivalent doses (MED) (mg/kg/day); and (3) to describe the pain scores (PS)., Results: Twenty-eight percent of inpatients used opioid PCA for pain control during the last 2 weeks of life. The mean MED (mg/kg/day) (SD) at 2 weeks prior and the day of death were 10.7 (17.9) and 19 (25.8). The mean MED increased over the last 2 weeks of life for all patients and across age groups and cancer diagnoses (all P < 0.05). The mean MED was significantly higher in the younger age group (age <13 vs. age ≥ 13) on the day of death (P < 0.04). There was a significant change in mean PS over the last 2 weeks of life (P < 0.001), with the highest PS on the day before death. The most frequently used concurrent medications were benzodiazepines (91%)., Conclusions: Children and young adults with cancer experience high opioid requirements and significant dose increases during the last 2 weeks of life. Additionally, PS increase toward the end of life. Opioid rotation and addition of adjuvant medications merit consideration in the context of escalating opioid requirements., (© 2015 Wiley Periodicals, Inc.)

We describe the effect and side effects in two children with cancer treated with intravenous methadone in extreme doses (>10 mg/kg/day) due to vincristine-induced neuropathy where surgical procedures provoked severe neuropathic pain. The maximum daily dose was 33 and 25 mg/kg/day. Methadone remained effective at adjusted doses. Few side effects were reported. No significant changes in paraclinical data were observed. Prolonged QTc-interval occurred only during concomitant treatment with fluconazole. In conclusion, methadone should be seen as a part of the armamentarium against cancer-related pain. Methadone can be used in extreme doses with appropriate monitoring by clinicians experienced in its use., (© 2015 Wiley Periodicals, Inc.)

Although opioid-induced hyperalgesia (OIH) is mentioned as a potential cause of opioid dose escalation without adequate analgesia, true evidence in support of this notion is relatively limited. Most studies conducted in the context of acute and experimental pain, which seemingly demonstrated evidence for OIH, actually might have measured other phenomena such as acute opioid withdrawal or tolerance. OIH studies in patients with chronic pain have used various experimental pain models (such as cold pain tolerance or heat pain intensity). Therefore, the fact that they have yielded inconsistent results is hard to interpret. Thus far, with the exception of a few clinical case reports on OIH in patients with cancer pain and one prospective study in patients with chronic neuropathic pain, evidence for OIH in patients with chronic or cancer-related pain is lacking. Whether experimental pain models are necessary for establishing the clinical diagnosis of OIH, and which specific model is preferred, are yet to be determined., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Morphine is widely used in cancer care, and understanding the concerns and perceptions of patients, family and friends is vital to managing pain and distress effectively. The 'myths of morphine' have frequently been discussed in medical literature, yet the extent to which such views are held is not clear. This qualitative project explores the perceptions and attitudes of the wider community towards morphine use in cancer care, to understand this 'mythology' according to those who in the future may themselves require its use., Methods: Semi-structured interviews were held with patients presenting to a metropolitan general practice clinic in Melbourne, Australia. A grounded theory framework underpinned the data collection and thematic analysis undertaken., Results: Interviewees (15) were aged 24-81, with a variety of experiences with cancer care and previous morphine use. Interviewees were highly supportive of morphine use in cancer care, with this attitude founded on the perceived severity of cancer pain and the powerful nature of morphine. They described a number of reasons morphine may be used in cancer care: to treat pain, to enable peace and also as a treatment for cancer., Conclusion: The public view of morphine to emerge from this study is markedly different from that discussed in the myths of morphine. It is viewed as a medication that has the ability to provide peace and control both pain and the course of cancer. The participants in this study described a wish for greater involvement in pain control decisions, perceiving morphine as a facilitator rather than a barrier to good cancer care.

Context: There is wide interindividual variation in response to morphine for cancer-related pain; 30% of patients do not have a good therapeutic outcome. Alternative opioids such as oxycodone are increasingly being used, and opioid switching has become common clinical practice., Objectives: To compare clinical response to oral morphine vs. oral oxycodone when used as first-line or second-line (after switching) treatment in patients with cancer-related pain., Methods: In this prospective, open-label, randomized, controlled trial (ISRCTN65155201) with a selected crossover phase, patients with cancer-related pain were randomized to receive either oral morphine or oxycodone as first-line treatment. Dose was individually titrated until the patient reported adequate pain control. Patients who did not respond to the first-line opioid (either because of inadequate analgesia or unacceptable adverse effects) were switched to the alternative opioid., Results: Two hundred patients were recruited. On intention-to-treat analysis (n = 198, morphine 98, oxycodone 100), there was no significant difference between the numbers of patients responding to morphine (61/98 = 62%) or oxycodone (67/100 = 67%) when used as a first-line opioid. Similarly, there was no significant difference in subsequent response when patients were switched to either morphine (8/12 = 67%) or oxycodone (11/21 = 52%). Per-protocol analysis demonstrated a 95% response rate when both opioids were available. There was no difference in adverse reaction scores between morphine and oxycodone either in first-line responders or nonresponders., Conclusion: In this population, there was no difference between analgesic response or adverse reactions to oral morphine and oxycodone when used as a first- or second-line opioid. These data provide evidence to support opioid switching to improve outcomes., (Copyright © 2015. Published by Elsevier Inc.)

Introduction: Pain is commonly experienced by patients with cancer, particularly those with advanced disease. Alleviating pain is an important goal of cancer treatment. Opioids are the cornerstone of the analgesic treatment., Areas Covered: Pharmacology, characteristics, and use of opioids in clinical practice are presented., Expert Opinion: Although the use of opioids is largely accepted as a fundamental step for controlling cancer pain, existing data supporting this statement are poor. All opioids provide analgesia and are effective in controlling cancer pain. New drugs have been developed and experience is accumulating among clinicians. Despite these drugs having different pharmacokinetic and chemical properties, there is no proof that one opioid is better than another one. Thus, the optimum benefit depends on the experience of the users. Clinicians should weight evidence, clinical experience, patient preferences, and treatment costs when choosing the optimal treatment for an individual patient with cancer pain. New opioids with specific receptor activities are under investigation.

Context: Studies of opioid use in cancer patients have been cross-sectional or have focused on mean consumption over a specific time interval., Objectives: This study aimed to determine the temporal pattern of prescribed opioids at a population level., Methods: Using Quebec administrative databases, we ascertained details of cancer-related deaths and filled community-based opioid prescriptions (COPs) in 48,420 decedents from 2003 to 2006., Results: Using group-based trajectory modeling, based on when people started to fill COPs, our population-based study demonstrated patterns of filled COPs with six distinct trajectories. An earlier start in opioid consumption resulted in a higher group average morphine daily dose; those who were already filling COPs at study entry (5.2%) had a final dose of more than 300mg by the time of death. Remarkably, 58.8% of people had not filled COPs with a biweekly average greater than 1mg earlier than two weeks before death, marking the end of follow-up. Breast cancer in women, prostate or colorectal cancer in men, and younger age and multiple myeloma in both sexes were positively associated with earlier filling of COPs., Conclusion: Patients dying of cancer require increasing doses of opioids over time; although we cannot distinguish the relative contributions of disease progression and opioid tolerance, age and certain cancers seem related to this phenomenon. Given the potentially prohibitive cost of prospective epidemiological studies, more elaborate clinical administrative databases that include regular pain assessment are necessary to determine optimal opioid use and factors associated with dose increases over time at a population level., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Pediatric oncology patients often receive prolonged courses of opioids, which can result in constipation., Objectives: Comparing patients who received senna matched with similar patients who received other oral bowel medications, determine the subsequent risk of "problematic constipation," assessed as the occurrence of the surrogate markers of receiving an enema, escalation of oral bowel medications, and abdominal radiographic imaging., Methods: This was a retrospective cohort study of hospitalized pediatric oncology patients less than 21 years of age in 78 children's and adult hospitals between 2006 and 2011 who were started on seven consecutive days or more of opioid therapy and were started on an oral bowel medication within the first two days of opioid therapy. Clinically detailed administrative data were used from the Pediatric Health Information System and the Premier Perspective Database. After performing propensity score matching of similar patients who started senna and who started a different oral bowel medication, Cox regression modeling was used to compare the subsequent hazard of the surrogate markers., Results: The final matched sample of 586 patients averaged 11.5 years of age (range 0-20 years); 41.8% (n = 245) had blood cancer, 50.3% (n = 295) had solid tumor cancer, and 7.9% (n = 46) had brain cancer. Initiating senna therapy within two days of starting the prolonged opioid course, compared with initiating another oral bowel medication, was significantly associated with a lower hazard during the ensuing five days for receipt of an enema (hazard ratio [HR], 0.31; 95% CI, 0.11-0.91) or undergoing abdominal radiographic imaging (HR, 0.74; 95% CI, 0.55-0.98), was marginally associated with a lower hazard of oral bowel medicine escalation (HR, 0.78; 95% CI, 0.59-1.03), and overall was significantly associated with a lower hazard of the composite end point of problematic constipation (HR, 0.70; 95% CI, 0.56-0.88)., Conclusion: Initiating senna therapy, compared with other oral bowel medications, diminishes the subsequent risk of surrogate markers of problematic constipation in this population., (Copyright © 2014 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Managing cancer pain often requires opioid medications, such as fentanyl, which is frequently initiated parenterally, and then converted to transdermal form. Little evidence exists to guide this conversion., Objectives: To observe the efficacy and safety of a six-hour continuous overlap method for converting intravenous fentanyl (IVF) to transdermal fentanyl (TF) in patients with cancer pain., Methods: We switched from IVF to TF using a 1:1 (IVF:TF) conversion ratio and overlapped a continuous, nontapered dose of IVF until six hours after TF placement. Pain intensity by Numeric Rating Scale, number of rescue analgesic doses, and presence and severity of opioid-related adverse events were recorded immediately before TF placement, and at six, 12, 18, and 24 hours thereafter., Results: A total of 17 consecutive patients with cancer pain controlled on IVF were converted to TF. Median age was 65 years, 10 were female, and all had Stage IV cancer. Pain intensity at six and 24 hours remained stable; a slight but statistically significant increase in Numeric Rating Scale was noted at 12 and 18 hours (P=0.01 and 0.02, respectively); however, there was no significant increase in number of rescue doses throughout the observation period. Only one patient experienced opioid-related adverse events., Conclusion: A continuous six-hour overlap method is a safe and effective strategy when converting from IVF to TF in patients with cancer pain. A slight increase in pain intensity may occur, but does not lead to increased rescue doses., (Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Context: Data on cancer outpatients undergoing opioid rotation (OR) are limited. Understanding the characteristics of patients who do not follow up after OR could facilitate optimization of OR., Objectives: To compare the characteristics and overall survival of patients with and without follow-up after OR., Methods: In this preliminary ad hoc analysis, we reviewed consecutive patients who presented to our supportive care center in 2008 for OR. Data about demographics, scores on the Edmonton Symptom Assessment System and Memorial Delirium Assessment Scale (MDAS), opioid use, and indications for OR were collected. Univariate logistic regression models were used to determine the factors associated with follow-up. Kaplan-Meier curves were used to evaluate survival., Results: Of the 190 patients who underwent OR, 120 (63%) had a follow-up visit. Follow-up visits occurred more frequently in patients with localized disease (89%; 24/27; P = 0.0023), history of substance abuse (100%; 12/12; P = 0.0085), performance status ≤ 2 (66%; 97/146; P = 0.0002), no delirium (67%; 118/177; P = 0.002), and uncontrolled pain as reason for OR (66%; 97/146; P = 0.036). Patients who underwent OR for opioid-induced neurotoxicity (44%; 15/34; P = 0.01) and had higher MDAS scores (P = 0.0009) were less likely to follow up. Both follow-up after OR (P < 0.001) and successful OR (P = 0.012) were associated with longer overall survival, with a difference in median survival of 4.3 and 3 months, respectively., Conclusion: Our preliminary study suggests that patients with advanced cancer, poorer performance status, opioid-induced neurotoxicity, and higher MDAS scores are less likely to follow up after OR and may have shorter overall survival and, therefore, require closer follow-up. Patients with unsuccessful OR also may have a shorter overall survival. Further studies are warranted., (Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Context: As patients with cancer are living longer, there is a need to ensure that treatments used for palliative care are well tolerated and effective during long-term use., Objectives: To investigate the long-term use of fentanyl pectin nasal spray (FPNS) for the treatment of breakthrough pain in cancer (BTPc) in patients receiving regular opioid therapy., Methods: Adult patients (N = 401) taking at least 60 mg/day oral morphine or equivalent, experiencing one to four episodes of BTPc a day, entered an open-label long-term study (NCT00458510). Patients had either completed an FPNS randomized controlled trial or were newly identified. Of these, 171 patients continued into an extension study. Up to four episodes of BTPc a day were treated with FPNS at 100-800 μg titrated doses. During the extension study, patients visited the clinic every four weeks for assessment and reporting of adverse events (AEs)., Results: There were 163 patients with documented FPNS use. The mean duration of use was 325 days; 46 patients used FPNS for ≥360 days; the maximum duration was 44 months. Seventy percent of patients did not change their FPNS dose; 2% of patients withdrew from the study because of the lack of efficacy. The most common AEs, aside from disease progression, were insomnia, 9.9%; nausea, 9.4%; vomiting, 9.4%; and peripheral edema, 9.4%. The overall incidence of FPNS-related AEs was 11.1%, the most common being constipation (4.1%), with no apparent dose relationship. Ten patients (5.8%) experienced nasal AEs, most of which were mild or moderate., Conclusion: FPNS appeared to provide sustained benefit and was well tolerated during long-term treatment of BTPc., (Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Introduction: Pain is a symptom of cancer and is categorized in two forms: background pain to be treated with analgesics, and breakthrough cancer pain (BTcP), which needs drug treatment on demand. We present a cost-effectiveness analysis of transnasal fentanyl citrate as an alternative to morphine., Methods: A Markov model considers a cohort of 100 patients on a daily basis. Effectiveness was included by selecting three clinical studies. Side effects, hospitalizations and visits were valued by referring to national formularies. Utility data were used to differentiate the health status inherent to BTcP., Results: The incremental cost-effectiveness ratio of transnasal fentanyl citrate is 10,140 euros/QALY. Sensitivity analysis shows that with a threshold of 30,000 euros/QALY, the treatment of BTcP with transnasal fentanyl citrate would have an 86% probability of being cost-effective., Conclusion: Transnasal Fentanyl citrate is cost-effective, therefore represents a good investment in health.

Purpose: Opioids are the mainstay of analgesic therapy in patients with cancer-related pain. While many of the side effects of opioids are well documented, the effect on the hypogonadal axis is less well understood. The aim of this systematic review is to examine the relationship between opioid therapy and hypogonadism in patients with cancer., Methods: An electronic search of the following databases was undertaken: MEDLINE, Embase and CINAHL from 1974 to August 2013. To be eligible for inclusion, studies had to meet the following criteria: adult patients (>18 years) with cancer taking any opioid by any route for any duration, gonadal function measured and the relationship between opioid use and gonadal function examined. All potentially eligible papers were reviewed independently and data extracted using a pro forma., Results: Four studies met the inclusion criteria. Due to the heterogeneous nature of the studies, it was not possible to amalgamate the results. Three studies suggested a relationship between opioid use and hypogonadism in patients with cancer. These studies also suggested this relationship to be dose dependent. There was evidence to suggest that hypogonadism was symptomatic and associated with reduced survival. One study showed no link between opioids and hypogonadism., Conclusions: Studies conducted have suggested an association between opioids and hypogonadism in patients with cancer. This warrants further investigation. A longitudinal study examining the impact of opioids on the hypogonadal axis would be of interest.

Context: Rapid-onset opioids for treating breakthrough pain (BTP) in patients with cancer are needed in the Japanese care setting., Objectives: To examine the efficacy and safety of fentanyl buccal tablets (FBTs) for treating BTP in Japanese cancer patients., Methods: This was a randomized, double-blinded, placebo-controlled study. In subjects receiving around-the-clock (ATC) opioids at doses of 30 mg or more to less than 60 mg or 60-1000 mg of oral morphine equivalents (low and high ATC groups), dose titration was started from 50 to 100 μg FBT, respectively. Subjects whose effective dose was identified were randomly allocated to a prearranged administration order of nine tablets (six FBTs and three placebos), one tablet each for nine episodes of BTP (double blinded). Efficacy and safety of FBT were assessed for patients overall, and also for the low and high ATC groups., Results: A significant difference was observed between FBT and placebo for the primary endpoint of pain intensity difference at 30 minutes. The analgesic onset of FBT was observed from 15 minutes in several secondary variables (e.g., pain relief). Adverse events were somnolence and other events associated with opioids were mostly mild or moderate. Of the low and high ATC group subjects, an effective FBT dose was identified in 72.2% and 73.1%, respectively., Conclusion: The safety of FBT and its analgesic effect on BTP were confirmed in Japanese cancer patients receiving opioids. Our findings suggest that analgesic onset may occur from 15 minutes after FBT, and that FBT can be administered to patients with low doses of ATC opioids., (Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Context: With many medications available for the management of breakthrough cancer pain (BTCP), physicians may require additional guidance in selecting an appropriate medication to suit an individual patient's needs., Objectives: To identify all the evidence and assess the relative clinical value of currently approved BTCP medications., Methods: Following a systematic literature search (2007-2010), the results of 10 randomized controlled trials investigating the effects of BTCP medications (intranasal fentanyl spray [INFS], fentanyl pectin nasal spray, fentanyl sublingual tablets, fentanyl buccal soluble film, fentanyl buccal tablets, oral transmucosal fentanyl citrate, and morphine sulfate immediate release) were synthesized using a network meta-analysis. The main outcome was pain intensity difference (PID) relative to placebo up to 60 minutes after the intake of medication., Results: INFS, fentanyl pectin nasal spray, fentanyl buccal tablet, and oral transmucosal fentanyl citrate showed greater PIDs relative to placebo than other BTCP medications 15 minutes after intake. All other medications showed greater PIDs relative to placebo at 30 minutes, except morphine sulfate immediate release, which did not show efficacy over placebo until 45 minutes. Only INFS produced clinically meaningful pain relief (absolute PID ≥2) at 15 minutes., Conclusion: From current evidence, although all BTCP medications provided pain relief within the time frames assessed, transmucosal fentanyl medications achieved a greater level of pain relief in a shorter time frame than placebo or oral morphine., (Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Objectives: As guidelines for opioid use in renal-impaired patients with cancer are limited, the authors sought to assess the efficacy, safety, and tolerability, of transdermal buprenorphine for moderate/severe cancer pain in renal-impaired outpatients., Methods: In a prospective parallel-group active-controlled study, n = 42 consecutively recruited outpatients with or without renal impairment (serum creatinine ≥1.3 or ≤1.2 mg/dL, respectively) were treated with transdermal buprenorphine (group BUP) or fentanyl (group FEN), respectively. Patients were followed up, at home, by the nonprofit ANT-Italia-foundation physicians in Bologna, Italy. Measurements at 10 (T1), 30 (T2), and 90 (T3) days after enrollment (T0) were pain intensity (Numerical Rating Scale [NRS]), Karnofski score, opioid dose (μg/h), rescue-dose consumption, and occurrence of adverse effects. Patients recorded subjective measurements in a personal diary. Upon data analysis, investigators were blinded to the patient group., Results: At T0, in groups BUP and FEN, median NRS score was 8.0 (CI, 7.4-8.4); its reduction over time (T3; NRS = 3.0; CI, 2.1-3.8 and 2.0-4.0, respectively) was significant and constant in both groups (t-test; T0-T1, T1-T2, and T2-T3; p < 0.0001, p < 0.001, and p < 0.05, respectively). At all times, there were no significant differences in pain scores between the groups. In all evaluations, adverse effects were reported n = 73/126 times (60.8 percent) and showed no significant association (X(2), p > 0.05) with the study groups., Conclusions: Transdermal buprenorphine, in outpatients with cancer and renal impairment, is as effective, safe, and tolerable as fentanyl in patients without such impairment. These results add further evidence to the notion that buprenorphine, with its peculiar pharmacokinetics, may be an appropriate choice for opioid treatment in patients with renal impairment.