Evidence on the analgesic role of bisphosphonates and denosumab in the treatment of pain due to bone metastases: A systematic review within the European Association for Palliative Care guidelines project.

BACKGROUND: Bisphosphonates and denosumab are well-established therapies to reduce the frequency and severity of skeletal-related events in patients with bone metastasis. However, the analgesic effect of these medications on bone pain is uncertain. AIM: To identify, critically appraise and synthesize existing evidence to answer the following questions: 'In adult patients with metastatic bone pain, what is the evidence that bisphosphonates and denosumab are effective and safe in controlling pain?' and 'What is the most appropriate schedule of bisphosphonate/denosumab administration to control bone pain?'. This review also updates the 2002 Cochrane review 'Bisphosphonates for the relief of pain secondary to bone metastases'. DESIGN: Standard systematic review and narrative synthesis. DATA SOURCES: MEDLINE, EMBASE and Cochrane CENTRAL databases were searched for relevant articles published through 31 January 2014. A manual search was also performed. Study inclusion criteria were: a) conducted in adult patients; b) randomized controlled trial or meta-analisys; c) reported efficacy of bisphosphonates or denosumab on pain and/or decribed side effects versus placebo or other bisphosphonate; and d) English language. RESULTS: The database search yielded 1585 studies, of which 43 (enrolling 8595 and 7590 patients, respectively, in bisphosphonate and denosumab trials) met the inclusion criteria. Twenty-two (79%) of the 28 placebo-controlled trials found no analgesic benefit for bisphosphonates. None of the denosumab studies assessed direct pain relief. CONCLUSION: Evidence to support an analgesic role for bisphosphonates and denosumab is weak. Bisphosphonates and denosumab appear to be beneficial in preventing pain by delaying the onset of bone pain rather than by producing an analgesic effect per se.

Efficacy and Safety of Methadone as a Second-Line Opioid for Cancer Pain in an Outpatient Clinic: A Prospective Open-Label Study.

INTRODUCTION: Most clinical reports on methadone rotation describe outcomes in hospitalized patients. The few studies that have included outpatients are retrospective. The aim of this study was to assess the efficacy and safety of methadone as a second-line opioid in adult patients with advanced cancer after rotation in routine clinical practice at a palliative care outpatient clinic. PATIENTS AND METHODS: This was a prospective, open-label study of 145 patients whose treatment was rotated from other opioids to methadone. Informed consent was obtained in all cases. The main outcome measure was change in the variable "worst pain" at day 28. Pain and pain interference were assessed with the Brief Pain Inventory, with side effects evaluated according to the Common Terminology Criteria for Adverse Events version 3.0. Pain levels were evaluated at study entry and at days 3, 7, 9, 14, 21, and 28. RESULTS: Rotation to methadone was performed for the following reasons: poor pain control (77.9%), opioid side effects (2.1%), or both (20%). The mean daily oral morphine equivalent dose before rotation was 193.7 mg. The median worst and average pain scores decreased significantly (p < .0001) from baseline to day 28: The median worst pain score decreased from 9 (interquartile range [IQR]: 8-10) to 6 (IQR: 3-8), and the median average pain score decreased from 6 (IQR: 5-7) to 4 (IQR: 2-5). The proportions of patients with moderate to severe worst and average pain decreased by 30.3% and 47.5%, respectively, by day 28. No increase in opioid toxicity was observed during the study. CONCLUSION: In outpatients with advanced cancer, rotation to methadone as a second-line opioid was efficacious and safe when using a tiered scheme with close follow-up by experienced health professionals. IMPLICATIONS FOR PRACTICE: The results of this study, conducted prospectively under real clinical conditions, support the efficacy and safety of oral methadone as a second-line opioid in ambulatory patients with cancer. Moreover, these findings corroborate previously reported outcomes in retrospective outpatient studies and prospective studies that evaluated inpatient populations. Although more research into methadone rotation strategies is still needed, this study describes a successful tiered scheme of oral methadone rotation that was proven safe and effective during follow-up.

Lidocaine 5 % patches as an effective short-term co-analgesic in cancer pain. Preliminary results.

PURPOSE: To analyze the short-term efficacy and patients' subjective perception of the use of lidocaine 5 % patches for painful scars (post-thoracotomy and post-mastectomy) and pain caused by chest wall tumors. METHODS: This is a prospective, descriptive, non-controlled, non-randomized, open-label study of patients seen in the palliative care outpatient clinic. Demographic data, variables relating to the severity of the pain, and concomitant therapy both at the start and end of treatment, the need for interventional anesthetic techniques (IAT), patients' subjective perception and treatment-related side effects were all recorded. RESULTS: Twenty patients were included with a mean follow-up of 29.2 days. The treatment led to a statistically significant clinical improvement in pain severity. There was no clinically significant opioid dose escalation during the treatment period. Only three patients required IAT to relieve the pain. Sixty five percent of patients were very satisfied with the therapy. No systemic or local adverse events were reported. CONCLUSIONS: The addition of lidocaine 5 % patches is effective in the short term for the treatment of neuropathic cancer pain accompanied by allodynia, whether deriving from a painful scar or chest wall tumor. These findings need to be confirmed by randomized controlled trials with larger samples.

Cancer-related neuropathic pain in out-patient oncology clinics: a European survey.

BACKGROUND: Although pain is frequently experienced by patients with cancer, it remains under-treated. The primary aim of this study was to estimate the prevalence of cancer-related neuropathic pain (CRNP) in patients with chronic pain who attended an outpatient clinic for standard care in Europe (irrespective of the reason or stage of the cancer). The secondary aims of this study were to characterise pain and cancer in patients with CRNP (including treatment) and to evaluate the usefulness of the painDETECT (PD-Q) screening tool to help physicians identify a potential neuropathic component of cancer-related pain. METHODS: An observational, non-interventional, cross-sectional, multi-centre study of adult patients with cancer using patient and physician case report forms (CRFs). Patients with CRNP were identified by physicians' clinical assessments after examining the completed PD-Q. RESULTS: A total of 951 patients visiting outpatient clinics across Europe were enrolled in this study between August 2010 and July 2011. Of these, 310 patients (32.60%; 95% confidence interval 29.62, 35.58) were identified as having CRNP. Twenty-nine of 39 (74.4%) physicians who completed the CRF relating to the PD-Q considered it a useful tool to help detect CRNP in daily practice and 28 of 39 (71.8%) indicated that they would use this tool in the future for most or some of their patients. Data from physicians before and after review of the completed PD-Qs showed a shift in clinical opinion (either to positive CRNP diagnosis [yes] or negative CRNP diagnosis [no]) in respect of 142 patients; about half of which (74) were categorised with an initial diagnosis of unknown. Opinions also shifted from a no to a yes diagnosis in 10 patients and from a yes to a no diagnosis in 51 patients. CONCLUSIONS: Approximately one-third of adults with cancer experiencing chronic pain attending outpatient clinics as part of routine care were considered to have CRNP in the opinion of the physicians after considering scores on the PD-Q. While physicians did not consider the PD-Q to be a useful tool for all patients, shifts in diagnosis before and after the use of this tool indicate that it may help physicians identify CRNP, especially where there is initial uncertainty.

Health resource utilisation associated with skeletal-related events in European patients with lung cancer: Α subgroup analysis from a prospective multinational study.

Bone complications or skeletal-related events (SREs), typically defined as radiation to bone, pathological fractures, surgery to bone and spinal cord compression, occur frequently in patients with bone metastases. As the survival of patients with advanced lung cancer improves, preventing SREs is becoming increasingly clinically relevant. The aim of this analysis was to assess the impact of SREs on health resource utilisation (HRU) in European lung cancer patients with bone metastasis. This multinational, observational study included patients who had at least one SRE in the 97 days prior to enrolment, a life expectancy of ≥6 months and an Eastern Cooperative Oncology Group performance status of 0-2. Data on HRU were retrospectively collected for up to 97 days prior to enrolment with a planned prospective follow-up for up to 18-21 months. The HRU measures included the number and length of inpatient hospitalisations and the number of outpatient visits and procedures. The investigators determined whether each HRU was attributable to a SRE. In total, 135 patients with lung cancer, enrolled at centres in Germany, Italy, Spain and the United Kingdom, contributed 214 SREs to this analysis. The median length [quartile (Q)1, Q3] of follow-up ranged from 1.5 (0.7, 3.3) to 5.6 (2.0, 8.2) months across the countries. Overall, 41% of the SREs required an inpatient stay, with a median (Q1, Q3) duration of 19.0 (6.0, 28.0) days. Spinal cord compression and surgery to bone were the SRE types most frequently requiring inpatient stays. Radiation to bone was associated with the largest number of outpatient visits and procedures. All the SREs resulting from bone metastases in patients with lung cancer contribute considerably to HRU and efforts to minimise the incidence of bone complications in these patients through appropriate treatments may help reduce this burden.

Health Resource Utilization Associated with Skeletal-Related Events in Patients with Advanced Prostate Cancer: A European Subgroup Analysis from an Observational, Multinational Study.

This study aimed to increase the understanding of health resource utilization (HRU) associated with skeletal-related events (SREs) occurring in patients with bone metastases secondary to advanced prostate cancer. A total of 120 patients from Germany, Italy, Spain and the United Kingdom were enrolled in this observational study. They had bone metastases secondary to prostate cancer and had experienced at least one SRE in the 97 days before giving informed consent. HRU data were collected retrospectively for 97 days before enrolment and prospectively for up to 18-21 months. HRU, including the number and duration of inpatient hospitalizations, number of outpatient and emergency department visits and procedures, was independently attributed by investigators to an SRE. Of the 222 SREs included in this analysis, 26% were associated with inpatient stays and the mean duration per SRE was 21.4 days (standard deviation (SD) 17.8 days). Overall, 174 SREs (78%) required an outpatient visit and the mean number of visits per SRE was 4.6 (SD 4.6). All SREs are associated with substantial HRU. Preventing SREs in patients with advanced prostate cancer and bone metastases may help to reduce the burden to both patients and European healthcare systems.

Health resource utilization associated with skeletal-related events in patients with advanced breast cancer: results from a prospective, multinational observational study.

Patients with breast cancer and bone metastases often experience skeletal complications (skeletal-related events [SREs]: pathologic fracture, radiation to bone, surgery to bone or spinal cord compression). Prospective data on the health resource burden of SREs are needed for planning healthcare requirements and estimating the value of new treatments, but limited data are available. This prospective, observational study collected health resource utilization (HRU) data independently attributed to SREs by investigators. Eligible patients had bone metastases secondary to breast cancer, life expectancy ≥6 months, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and at least one SRE in the 97 days before enrollment. Data, collected retrospectively for 97 days before enrollment and prospectively for 18-21 months, included number and duration of inpatient stays, outpatient visits, emergency room visits and procedures. Altogether, 223 patients were enrolled from Germany, Italy, Spain and the UK. Of the 457 SREs, 118 (25.8%) were associated with inpatient stays. The mean duration of stay was 19.5 (standard deviation [SD] 19.2) days per SRE (based on 117 SREs). Surgery to bone and spinal cord compression were the SREs most likely to require inpatient stays (77.8% and 57.9% of SREs, respectively), while radiation to bone was the least likely (9.7%). Spinal cord compression required the longest inpatient stay per event (34.2 [SD 30.2] days) and radiation to bone the shortest (14.3 [SD 10.2] days). Overall, 342 SREs (74.8%) required an outpatient visit, with radiation to bone the most likely (85.7%), and surgery to bone the least likely (42.6%). Radiation to bone was also associated with the greatest number of outpatient visits per event (6.8 [SD 6.7] visits). All SREs were associated with substantial HRU therefore, preventing SREs in patients with breast cancer may reduce the burden imposed on healthcare systems.