Introduction
Patients with cancer may experience pain due to direct tumor effects (e.g., metastatic bone invasion) or from adverse events of treatments or pain associated with comorbidities ( 1 – 4 ). Bone invasion occurs in <95% of patients with multiple myeloma, 75% of patients with breast and prostate cancer, and 15–40% of patients with other types of tumors ( 5 – 7 ). Bone metastases are associated with morbidities, including severe pain, pathological fractures and other oncological emergencies. These skeletal-related events (SRE) have a major impact on quality of life ( 8 – 10 ).
Bone metastases are caused by upregulated osteoclastic activity, leading to increased bone resorption, and are a common source of pain. Bisphosphonates (BP) are selective inhibitors of osteoclastic bone resorption ( 11 ). BPs have been used for >15 years, and are known to reduce and delay osteoporosis and metastatic bone disease skeletal morbidity ( 12 , 13 ). Pamidronate (PAM) ( 14 , 15 ) and zoledronic acid (ZOL) are widely used BPs ( 8 , 16 – 22 ). More recently approved, denosumab is a human monoclonal antibody against the cytokine receptor-activated nuclear B ligand (RANKL). RANKL is involved in tumor cell migration and is a mediator of osteoclast differentiation and activation. Denosumab has also demonstrated efficacy in terms of pain palliation ( 11 , 23 ).
Despite pain guidelines, some patients still suffer from uncontrolled pain due to drug side effects or lack of efficacy, or analgesic tolerance, all of which may lead to treatment discontinuations ( 24 – 29 ). Lack of knowledge of health professionals ( 30 , 31 ), patient barriers precluding adequate treatment (e.g., fearing addiction), lack of compliance ( 32 , 33 ) and failure to diagnose specific pain syndromes ( 34 – 36 ) can all lead to underuse of pain medication ( 37 , 38 ). Different genetic predispositions for pain perception, metabolism, opioid receptors and transporters ( 39 ), may also result in failure of pain relief ( 40 , 41 ).
To accomplish successful pain treatment, evaluation, characterization and quantification of pain are required. The use of the Brief Pain Inventory (BPI) ( 42 , 43 ) is desirable in clinical practice, even outside of clinical trials ( 44 ). The scores obtained will allow more accurate comparisons between different evaluations of the same patient and patient subgroups ( 45 ). The aims of our study include the evaluation of metastatic bone pain, skeleton-related events and survival in a cohort of patients with cancer treated with intravenous BPs, crosschecks between patient pain reports [BPI and 36-Item Short Form Survey (SF-36)] and data from clinical files (pain narratives), and the influence of pain and these variables on clinical outcome and survival.
Patients and methods
Patient studies and questionnaires applied
Case selection was performed among patients undergoing BP treatment at the Day Hospital of our cancer center between November 2010 and March 2011. Recruitment included the first interview, self-filling of the BPI and SF-36 and baseline collection of data from clinical files. The patients' ability to understand the study was evaluated during the medical interview.
Although pain and quality of life were evaluated in a single interview, survival rate was determined in July 2016 (with review of medical records), to accomplish a 5-year follow-up. Breast and prostate cancer history determined a 5-year final follow-up evaluation.
Inclusion criteria were as follows: adult patients with histological confirmation of cancer with bone involvement; intravenous BP treatment (at least 1 intravenous administration); >1 month expected survival; ability to understand and answer written questionnaires; and permitting blood sample collection.
Ethical issues
Before any procedure was undertaken, all patients provided written informed consent. Ethical considerations were made as per local and national Ethics Committees and the Helsinki Declaration, and ethical approval was granted by the institutional commission of ethics.
Measures
Demographic and clinical characterization
Demographic information and clinical characteristics were collected from patient files. Performance status was assessed by Eastern Cooperative Oncology Group (ECOG) score ( 46 ). Analgesic treatment categorization was performed according to the WHO analgesic ladder: i) Non-opioid drugs (anti-inflammatory drugs or acetaminophen); second; ii) weak opioid drugs (tramadol and codeine), and iii) strong opioid drugs (fast or slow-acting morphine or equivalent patches) ( 47 , 48 ). Invasive procedures were presented with other analgesic techniques ( 49 , 50 ). The daily dose of morphine was based on patient reported consumption in the BPI and clinical files, using an Opioid Morphine Equivalent Conversion adapted from R. Sittle and N. Griesinger ( 51 ).
Pain and quality of life evaluation
BPI is a numerical scale with 11-points, used to measure pain intensity from 0–10 (worst pain imaginable), and functional interference from 0–10 (complete interference) ( 42 , 43 ). Using ‘last week’ as a temporal reference, the BPI questionnaire facilitates pain characterization at different levels: Maximum, minimum, average and right now ( 43 , 44 , 52 ). Rating pain intensity as mild, moderate or severe was performed using the answers for ‘maximum pain’ according to the BPI authors' proposal; mild, score of 1–4; moderate, score of 5–6, and severe, score of 7–10 ( 44 , 52 , 53 ). Quality of life was evaluated using the 36-Item Short Form Health Survey ( 42 , 54 ).
Statistical analysis
Data were analyzed using SPSS software (version 17.0; SPSS, Inc., Chicago, IL, USA). The χ 2 and log-rank tests were used. Independent prognostic factors were assessed using Cox-regression, with calculation of hazard ratios and 95% confidence interval (CI). P<0.05 was considered to be statistically significant. Survival curves were constructed using the Kaplan-Meier (KM) method and the log-rank test was used to compare differences in survival. SRE-free survival was defined as the time elapsed from diagnosis of the first bone metastases to the first SRE (SRE were considered to be events). Pathological fractures, spinal cord compression, radiotherapy of bone metastasis, neurological or orthopedic surgery and tumor-related hypercalcemia were considered to be SREs. A fracture treated with surgery and radiotherapy was considered to be a single event ( 8 , 9 ). Overall survival (OS) was defined as the time elapsed from diagnosis to mortality or last day of follow-up (mortality due to any cause was considered an event).
Results
Authors interviewed 186 patients, but only 84 returned questionnaires with valid answers (45% patients surveyed). Using clinical files, 79 cases (94%) demonstrated reference to pain, 6 demonstrated pain absence, 38 demonstrated only pain location, and 10 suggested irruptive pain. Regarding intensity evaluation, moderate to severe pain ( 13 ) and mild pain ( 12 ) were reported. A total of 7 patients were lost to follow-up.
Population characterization and cancer evaluation (n=84)
Table I lists the social and demographic characteristics of the patients (n=84). All patients were Caucasian, 64% were female and 77% were >50 years old (median 62, range 34–85). Sociocultural information was limited, the most common occupation was ‘work at home’ (n=18), 8 patients had a university degree (9.5%), 22 had technical training (26%) and 2 had a military career (2.4%). The social network was unstable in 10 cases (12%) and based on spouse and children in 47 cases (56%).
The most frequent types of cancer were breast, prostate and multiple myeloma. A total of 28 patients (33.3%) exhibited bone involvement at diagnosis (including 13 myeloma cases) and 5 exhibited metastasis outside the bone (solid stage IV tumors, n=20). The median time interval from diagnosis to bone metastasis was 23 months (range, 2–91). In patients with solid tumors (n=71), 48 (68%) demonstrated synchronous or metachronous disease out of the bone (non-visceral, n=19; visceral, n=15, or both, n=14).
A total of 52 patients had diagnoses of SRE. The most frequent was radiotherapy (n=24; 46% of the total of SRE). There were 15 vertebral fractures, 1 femoral neck fracture, 12 cases of spinal cord compression syndrome and 3 cases of symptomatic hypercalcemia. The relationship between total SRE number and the impact on ECOG was significant (P<0.001).
Analgesic and BP treatment (n=84)
Analgesic treatment was recorded according to the WHO ladder ( Table I ). A total of 45 patients (46%) had not been prescribed analgesic drugs, including 2 patients prescribed only adjuvant drugs. Tramadol was used to treat 22 patients, 10 patients were treated with tramadol with acetaminophen, 8 patients were treated by morphine sustained release and 5 with a transdermal patch (3 with fentanyl and 2 with buprenorphine). The median time interval since the beginning of opioid treatment was 9 months (range, 1–54), and the average daily dose was 98 mg (range, 60–180). Adjuvants were used to treat 51 patients (60.7%) and 44 patients (52.4%) were prescribed drugs to supportive care of adverse events. Unfortunately, pain treatment was unclear in 12 cases (14.3%). χ 2 analysis revealed that a significant association was identified between adequate treatment and complete pain evaluation (P=0.031). Only 7 patients (8.3%) had been assessed by the Pain Unit.
Intravenous PAM was the most commonly prescribed drug (n=63). BP was introduced at the time of first SRE or later in 26 patients. The median time from the start of BP treatment to the first SRE was 14 months (1–83). Dental problems were reported in 24 patients and 50% patients underwent a dental consultation prior to BP treatment. BP interruptions (n=25, 30%) were due to dental treatment (n=16), jaw osteonecrosis (n=3), impaired kidney function (n=4) or bone marrow transplantation (n=2).
Pain and quality of life evaluation (n=80)
BPI overall incidence of pain was 91.6% (considering answers to ‘maximum pain’ during the last week, n=80), including 27.5% reporting mild pain, 27.5% reporting moderate pain and 36.2% reporting intense pain ( Tables II – IV ). For the ‘minimum pain’ question, 24% patients reported moderate and 32% reported severe pain. For the ‘pain right now’ question, a statistically significant difference was demonstrated between the answers to the different questions (P<0.001). A total of 32 patients (38%) performed BPI evaluation before the first SRE.
Only 1 patient reported complete relief with therapy and 54% reported pain reduction >50%. A total of 32 patients reported insufficient relief (0–40%), 22 reported moderate relief (50–60%) and 20 reported significant relief (70–100%). A total of 27 patients, 53% of those reporting moderate to severe pain, underwent opioid treatment, with 16% treated with a strong opioid ( Tables III and IV ).
Cancer pain severity affects general activity (P<0.001), mood (P=0.001), ability to walk (P=0.001), ability to perform normal work (P<0.001) and the joy of living (P=0.033). As pain intensity increases, interference with daily activities also increases (score ≥5). No statistically association was identified in terms od sleep, social relationships and reported pain vs. therapeutic regimen ( Tables III and IV ). Table V presents relevant data from the SF-36 Quality of Life Questionnaire is presented. The adherence to self-fulfilling was lower than that of the BPI assessment.
Breast cancer subgroup
A total of 49 patients (58%) had a primary tumor of the breast, the median age of whom was 58 years (range, 34–85) and only 2 patients had triple negative tumors ( Table VI ). Twelve patients presented with bone metastases at diagnosis (24.5%). At the time of BPI completion, 29 patients (59.2%) presented with disseminated predominantly blastic bone disease. 1 SRE was recorded for 27 patients (55.1%) and ≥1 in 4 patients (8.2%). The mean value of CA 15.3 was 244 U/ml (range, 12–2246), with 9 patients presenting normal values (<30 U/ml). The median time interval since diagnosis was 70 months (range, 6–278) and the median time interval since bone metastasis was 27 months (range, 4–91). In BPI, 31 patients reported moderate or severe pain (63.26%) and in the Quality of Life Questionnaire, 22 patients reported feeling happy for a ‘small part of the time’ or ‘never’ (>50%). Only 6 patients underwent treatment with strong opioid (12%). There were no statistically significant differences in terms of pain severity among the different characteristics of this subgroup.
Survival data (n=84)
To better understand cancer burden and treatment outcomes, a 5-year period was considered for survival time. In 2011, when the 84 questionnaires were completed, only 4 patients suffered mortality. OS analysis revealed a statistically significant association between tumors (P=0.035) and stage at diagnosis (P<0.001) with OS. ECOG was also significantly associated with OS (P=0.002). Data regarding ‘maximum pain’ during the last week was analyzed in terms of OS, and a statistically significant association was identified in the male subgroup, with decreased survival associated with patients with intense pain (P=0.004). Average SRE-free survival was 9 months (range, 4.39–13.73, 95% CI). Statistically significant differences between subgroups were identified for time since diagnosis of bone metastasis (P=0.005) in terms of SRE-free survival. A statistically significant association was found between stage at diagnosis and SRE-free survival (P<0.001), with decreased survival demonstrated for patients with stage IV disease. Neither OS nor SRE-free survival were associated with age, female sex, baseline anticancer treatment, SRE number, presence of visceral metastasis or other BPI answers (namely, number of pain locations).
Discussion
Adequate treatment of pain may be limited by the patient, health professional or national health system ( 25 , 30 – 33 ). To evaluate pain intensity, scales such as visual analog, numerical rating, faces or qualitative scales are the most frequently used procedures ( 3 , 30 , 53 , 55 , 56 ). Only 25/79 patients (31%) presented evaluation of pain intensity using these methodologies in the present study. Inventories aim to assess pain in a more comprehensive way, but they are time and resource consuming ( 3 , 43 , 44 , 52 ).
In the present study, breast and prostate cancer were the most prevalent, and multiple myeloma the least prevalent. This is consistent with the reported prevalence of the population ( 57 – 60 ). Furthermore, at diagnosis, 28% patients with solid tumors present with stage IV disease. Considering BPI results, overall pain incidence was 91.6%, higher than that previously reported for cancer patients ( 55 ). A total of 32 patients performed BPI prior to the first SRE. In March 2007, a systematic review was published, reporting an overall prevalence of cancer pain of 59% (95% CI, 44–73), using visual or numerical scaling, verbal characterization or simply ‘yes or no’ methods ( 56 ). In September of the same year (2007) a systematic review of 40 years of literature concluded that 64% of patients with advanced or metastatic cancer reported pain; 59% of patients receiving anticancer treatment reported pain, and a third of patients reported pain after completing curative treatment. These data suggest that the prognosis of the primary tumor and cancer burden may not be proportional to pain ( 56 ).
Although initial surveying took place in 2011, a 5-year follow up of survival was performed to determine disease aggressiveness as well as treatment outcomes (in addition to baseline data regarding disease, metastatic pattern and anticancer treatment).
Pain perception by patients may not be coincident with health professional evaluation. For example, we observed that 63.7% of patients reported moderate to severe pain by BPI, but this was only reflected in the clinical files of 15.4% patients. Only 5 patients were treated with strong opioids (17%) and 7 patients were assessed in the Pain Unit (8.3%). These data suggest that overconsumption of anti-inflammatory drugs to the detriment of opioids may explain why 73% of patients reported inadequate relief via BPI.
Our results suggest that BP and adequate analgesia were prescribed late in the course of disease (prescribed after first SRE in 31% patients). SRE number was statistically associated with the interval between of BP therapy and ECOG. The opioid of use, SRE and ECOG were demonstrated to impact patient capacity for self-care, general activity, ability to walk and performance of normal work.
In some countries, opioids are unavailable, and in others their abusive use has resulted in a period of opioid avoidance ( 41 ). We believe that the high prevalence of pain in the present population is associated with subdiagnosis, insufficient characterization and consequent misapplication of the analgesic pain scale. Cancer pain represents a particular entity and can be treated with the same approach as that for degenerative osteo-articular pathology, for example ( 25 , 32 , 48 , 61 ). The systematic and complete characterization of pain, using tools that allow for the assessment of severity with accuracy and reproducibility, poses an ethical issue. Cancer pain severity affects mood and quality of life, and has been suggested to be related to pain relief treatment.
Decreased survival times of male patients reporting intense pain were independent of primary disease or SRE number (considering answers to ‘maximum pain during the last week). This may be due to a number of reasons, including psychological, sociological and genetic differences. Males may experience a different perception of pain, or interact differently with healthcare professionals than females. Furthermore, we they may suggest that males present a better accuracy in pain characterization. In a recent report of health-related quality of life (EQ-5D-5L), it was concluded that men score increased mean values using the visual analog scale (VAS) than women, and that, overall, the VAS mean decreases with age ( 62 ). Santoro et al ( 63 ) found significant sex differences in regional brain glucose metabolism associated with opioid withdrawal. However, this study was performed in a different setting of patients and with a different treatment goal. It has been suggested that the clinical response to buprenorphine or methadone can depend on sex; with females having more success using pharmacological treatments for opioid dependence compared with males. Clinical treatment failure has been more commonly reported in males ( 63 ). Sex differences in terms of pain were also identified in patients with fibromyalgia and burning mouth syndrome ( 64 , 65 ). Future clinical trials should specifically address the variables associated with sex in cancer patients. The small number of male patients in the present study (n=30) is a limitation, and further investigation using a larger sample size is required.
The relationship between the total SRE number and the impact on ECOG was statistically significant. SRE number had a functional impact on the daily activities of the patients. Bone metastasis at diagnosis and ECOG impacted OS, independent of pain scores. Cancer pain severity affects general activity, ability to walk, performance of normal work, mood and quality of life. Breast and prostate cancer treatments have improved over the last decade; however, performance status and the biology of bone metastasis remain the determinant factors of survival. A recent study of non-small cell lung cancer (NSCLC) reported that patients with stage I–III disease treated with BPs had improved outcomes compared with those without treatment. However, no difference was observed for patients with stage IV disease. The authors concluded that the factors associated with OS and SRE-free survival of patients with NSCLC and bone metastases remain unknown ( 66 ).
The associations between BPI evaluation and clinical impacts are consistent with previous studies ( 44 , 67 ). Pain remains a serious public health problem. Despite published legislation and training of health professionals, pain characterization by medical interview and pain narratives are not exhaustive enough to facilitate correct or sufficient pain management, or to improve palliative care and costs to national health systems (particularly in Portugal) ( 23 ).
The overuse of unidimensional scales may compromise the evaluation process, to the extent that malignant bone pain becomes a subjective complaint, leading to difficulties in the establishment of quantitative values and corresponding normal cutoffs.
The use of BPI and other tools, such as quality of life questionnaires, can be effective for patients with cancer pain, and they are desirable in clinical practice. Male survival was associated with severe pain, which is consistent with recent data, which suggested that treatment failure is more commonly experienced by male. The potential significance of sex should be addressed in future study.
There are a number of limitations of the present study. The sample of cancer patients from a single cancer center was small, with only one single point assessment of BPI and SF-36. However, to the best of our knowledge, this is the first study to represent the Portuguese population with cancer. Although we considered primary disease, initial staging, baseline anticancer treatment, SRE number, the presence of visceral metastasis (in addition to bone disease) and 5-year survival, our results may be biased by variety in types of cancer and/or tumor burden. The prevalence of breast and prostate cancer was high in the present study. Therefore, the impact of pain on survival may be less influenced by cancer prognosis ( 68 ). A recent systematic review addressing the impact of pain on the survival of cancer patients revealed that pain can be an independent prognostic factor in advanced prostate cancer. The authors also highlighted the interference of opioid treatment, which was less prevalent in the present study ( 69 ). It is unclear from the existing literature whether severity of pain is associated with survival. The results of the present study may guide the design of further studies with more homogeneous populations and better estimations of tumor burden, to ultimately improve pain characterization and effective pain relief.
The present study reinforces the requirement for complete and accrued pain narratives, using BPI and quality of life questionnaires, in patients with cancer. Furthermore, it was suggested that these tools may contribute to the optimization of analgesia and may increase life expectancy. Further clinical studies and pain assessment data banks (with multiple evaluations of BPI and quality-of-life questionnaires or others tools) should be implemented to validate the importance of these tools.
Acknowledgements
The authors would like to thank Dr Ana Correia de Oliveira and all of the team of the Research Center-Molecular Oncology Group; Medical Oncology and Hematology Department, Unit of Study and Treatment of Pain, Teamwork of Daily Hospital and Blood Collection Station/Clinical Laboratory of Francisco Gentil Portuguese Institute of Oncology, Porto, Portugal for helping to identify potential patients.
Funding
The present study was developed as part of a project selected as an internal clinical research project of Francisco Gentil Portuguese Institute of Oncology, Porto, Portugal (Bulletin 8/2017, CI-IPOP 70/2017).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
CV collected all the data and performed the statistical analyses. MF, DP and RM interpreted the results, assisted with statistical analyses and manuscript writing. The final manuscript has been reviewed and approved by all authors.
Ethics approval and consent to participate
Ethical considerations respected local and national Ethics Committee and Helsinki Declaration. The study protocol was approved by Instituto Português de Oncologia do Porto Francisco Gentil (IPO-PORTO) ethical committee. All patients provided written informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
1 Marcus NJ Pain in cancer patients unrelated to the cancer or treatment Cancer Invest 23 84 93 2005 10.1081/CNV-46516 15779871
2 Williams AC Craig KD Updating the definition of pain Pain 157 2420 2423 2016 10.1097/j.pain.0000000000000613 27200490
3 Alcock MM Defining pain: Past, present, and future Pain 158 761 762 2017 10.1097/j.pain.0000000000000828 28301403
4 Izumi H Igishi T Yamasaki A Takeda K Yanai M Tanaka N Sakamoto T Nishii-Ito S Touge H Kodani M Development of fever following first administration of zoledronate as a prognostic factor in advanced non-small cell lung cancer patients with bone metastases Mol Clin Oncol 7 1000 1004 2017 29285363 10.3892/mco.2017.1447 PMC5740853
5 Roodman GD Mechanisms of bone metastasis N Engl J Med 350 1655 1664 2004 10.1056/NEJMra030831 15084698
6 Coleman RE Metastatic bone disease: Clinical features, pathophysiology and treatment strategies Cancer Treat Rev 27 165 176 2001 10.1053/ctrv.2000.0210 11417967
7 Luo Q Xu Z Wang L Ruan M Jin G Progress in the research on the mechanism of bone metastasis in lung cancer Mol Clin Oncol 5 227 235 2016 10.3892/mco.2016.917 27446555 PMC4950548
8 Bell R Efficacy of ibandronate in metastatic bone disease: Review of clinical data The oncologist 10 Suppl 1 S8 S13 2005 10.1634/theoncologist.10-90001-8 16264107
9 Fontanella C Fanotto V Rihawi K Aprile G Puglisi F Skeletal metastases from breast cancer: Pathogenesis of bone tropism and treatment strategy Clin Exp Metastasis 32 819 833 2015 10.1007/s10585-015-9743-0 26343511
10 Kolesnikov-Gauthier H Lemoine N Tresch-Bruneel E Olivier A Oudoux A Penel N Efficacy and safety of 153 Sm-EDTMP as treatment of painful bone metastasis: A large single-center study Support Care Cancer 26 751 758 2018 10.1007/s00520-017-3885-3 28920149
11 Vardy J Agar M Nonopioid drugs in the treatment of cancer pain J Clin Oncol 32 1677 1690 2014 10.1200/JCO.2013.52.8356 24799483
12 Aapro M Abrahamsson PA Body JJ Coleman RE Colomer R Costa L Crinò L Dirix L Gnant M Gralow J Guidance on the use of bisphosphonates in solid tumours: Recommendations of an international expert panel Ann Oncol 19 420 432 2008 10.1093/annonc/mdm442 17906299
13 Idota A Sawaki M Yoshimura A Hattori M Inaba Y Oze I Kikumori T Kodera Y Iwata H Bone Scan Index predicts skeletal-related events in patients with metastatic breast cancer Springerplus 5 1095 2016 10.1186/s40064-016-2741-0 27468396 PMC4947061
14 Pavlakis N Schmidt R Stockler M Bisphosphonates for breast cancer Cochrane Database Syst Rev CD003474 2005 10.1002/14651858.CD003474.pub2 16034900
15 Small EJ Smith MR Seaman JJ Petrone S Kowalski MO Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer J Clin Oncol 21 4277 4284 2003 10.1200/JCO.2003.05.147 14581438
16 Coleman RE Bisphosphonates: Clinical experience Oncologist 9 Suppl 4 S14 S27 2004 10.1634/theoncologist.9-90004-14 15459426
17 Rosen LS Gordon D Kaminski M Howell A Belch A Mackey J Apffelstaedt J Hussein MA Coleman RE Reitsma DJ Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: A randomized, double-blind, multicenter, comparative trial Cancer 98 1735 1744 2003 10.1002/cncr.11701 14534891
18 Wardley A Davidson N Barrett-Lee P Hong A Mansi J Dodwell D Murphy R Mason T Cameron D Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: A randomised, crossover study of community vs hospital bisphosphonate administration Br J Cancer 92 1869 1876 2005 10.1038/sj.bjc.6602551 15870721 PMC2361764
19 Shapiro CL Moriarty JP Dusetzina S Himelstein AL Foster JC Grubbs SS Novotny PJ Borah BJ Cost-effectiveness analysis of monthly zoledronic acid, zoledronic acid every 3 months, and monthly denosumab in women with breast cancer and skeletal metastases: CALGB 70604 (Alliance) J Clin Oncol 35 3949 3955 2017 10.1200/JCO.2017.73.7437 29023215 PMC5721226
20 Shapiro CL Himelstein AL Zoledronic acid dosing in patients with metastatic breast cancer JAMA Oncol 4 585 586 2018 10.1001/jamaoncol.2017.0789 29192317
21 Himelstein AL Loprinzi CL Shapiro CL Zoledronic acid dosing interval for metastatic cancer-reply JAMA 317 1478 2017 10.1001/jama.2017.2566 28399247
22 Himelstein AL Foster JC Khatcheressian JL Roberts JD Seisler DK Novotny PJ Qin R Go RS Grubbs SS O'Connor T Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: A randomized clinical trial JAMA 317 48 58 2017 10.1001/jama.2016.19425 28030702 PMC5321662
23 von Moos R Costa L Ripamonti CI Niepel D Santini D Improving quality of life in patients with advanced cancer: Targeting metastatic bone pain Eur J Cancer 71 80 94 2017 10.1016/j.ejca.2016.10.021 27984770
24 Burton AW Cleeland CS Cancer pain: Progress since the WHO guidelines Pain Pract 1 236 242 2001 10.1111/j.1533-2500.2001.01025.x 17134407
25 Varrassi G Müller-Schwefe G Pergolizzi J Orónska A Morlion B Mavrocordatos P Margarit C Mangas C Jaksch W Huygen F Pharmacological treatment of chronic pain-the need for CHANGE Curr Med Res Opin 26 1231 1245 2010 10.1185/03007991003689175 20337502
26 Lara-Solares A Ahumada Olea M Basantes Pinos ALÁ Bistre Cohén S Bonilla Sierra P Duarte Juárez ER Símon Escudero OA Santacruz Escudero JG Flores Cantisani JA Latin-American guidelines for cancer pain management Pain Manag 7 287 298 2017 10.2217/pmt-2016-0065 28326952
27 Yoshimoto T Tomiyasu S Saeki T Tamaki T Hashizume T Murakami M Matoba M; Symptom Control Research Group (SCORE-G): How do hospital palliative care teams use the WHO guidelines to manage unrelieved cancer pain? A 1-year, multicenter audit in Japan Am J Hosp Palliat Care 34 92 99 2017 10.1177/1049909115608810 26443717
28 Martínez-Nicolás I Ángel-García D Saturno PJ López-Soriano F Cancer pain management: Systematic review and critical appraisal of clinical practice guidelines Rev Calid Asist 31 55 63 2016 (In Spanish) 10.1016/j.cali.2015.06.009 26420516
29 Carlson CL Effectiveness of the World Health Organization cancer pain relief guidelines: An integrative review J Pain Res 9 515 534 2016 10.2147/JPR.S97759 27524918 PMC4965221
30 Sloan PA Donnelly MB Schwartz RW Sloan DA Cancer pain assessment and management by housestaff Pain 67 475 481 1996 10.1016/0304-3959(96)03152-1 8951944
31 Warncke T Breivik H Vainio A Treatment of cancer pain in Norway. A questionnaire study Pain 57 109 116 1994 10.1016/0304-3959(94)90114-7 8065787
32 Paice JA Toy C Shott S Barriers to cancer pain relief: Fear of tolerance and addiction J Pain Symptom Manage 16 1 9 1998 10.1016/S0885-3924(98)00025-6 9707652
33 Miaskowski C Dodd MJ West C Paul SM Tripathy D Koo P Schumacher K Lack of adherence with the analgesic regimen: A significant barrier to effective cancer pain management J Clin Oncol 19 4275 4279 2001 10.1200/JCO.2001.19.23.4275 11731509
34 Caraceni A Martini C Zecca E Portenoy RK Ashby MA Hawson G Jackson KA Lickiss N Muirden N Pisasale M Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey Palliat Med 18 177 183 2004 10.1191/0269216304pm890oa 15198130
35 Gustorff B Dorner T Likar R Grisold W Lawrence K Schwarz F Rieder A Prevalence of self-reported neuropathic pain and impact on quality of life: A prospective representative survey Acta Anaesthesiol Scand 52 132 136 2008 10.1111/j.1399-6576.2007.01486.x 17976220
36 Piano V Verhagen S Schalkwijk A Burgers J Kress H Treede RD Hekster Y Lanteri-Minet M Engels Y Vissers K Diagnosing neuropathic pain in patients with cancer: Comparative analysis of recommendations in national guidelines from European countries Pain Pract 13 433 439 2013 10.1111/papr.12018 23279302
37 Pergolizzi JV Jr Raffa RB Zampogna G Breve F Colucci R Schmidt WK LeQuang JA Comments and suggestions from pain specialists regarding the CDC's proposed opioid guidelines Pain Pract 16 794 808 2016 10.1111/papr.12475 27600924
38 Dueñas M Salazar A Sanchez M De Sola H Ojeda B Failde I Relationship between using clinical practice guidelines for pain treatment and physicians' training and attitudes toward patients and the effects on patient care Pain Pract 18 38 47 2018 10.1111/papr.12579 28371291
39 Skorpen F Laugsand EA Klepstad P Kaasa S Variable response to opioid treatment: Any genetic predictors within sight? Palliat Med 22 310 327 2008 10.1177/0269216308089302 18541635
40 Sakai K Matsuoka H Ohtake Y Makimura C Izumi H Fujita Y Otsuka M Tsurutani J Nishio K Nakagawa K Koyama A Incidence of carnitine deficiency in patients with cancer pain: A pilot study Mol Clin Oncol 6 331 333 2017 10.3892/mco.2017.1159 28451408 PMC5403195
41 Scarborough BM Smith CB Optimal pain management for patients with cancer in the modern era CA Cancer J Clin 68 182 196 2018 10.3322/caac.21453 29603142 PMC5980731
42 Azevedo LF Costa PA Dias C Agualusa L Lemos L Romão J Patto T Vaz-Serra S Abrunhosa R Carvalho CJ Tradução, adaptação cultural e estudo multicêntrico de validação de instrumentos para rastreio e avaliação do impacto da dor crónica Dor 15 6 56 2007
43 Cleeland CS Ryan KM Pain assessment: Global use of the brief pain inventory Ann Acad Med Singapore 23 129 138 1994 8080219
44 Cleeland CS O'Mara A Zagari M Baas C Integrating pain metrics into oncology clinical trials Clin Cancer Res 17 6646 6650 2011 10.1158/1078-0432.CCR-11-1109 22046026
45 Basch E Dueck AC Rogak LJ Minasian LM Kelly WK O'Mara AM Denicoff AM Seisler D Atherton PJ Paskett E Feasibility assessment of patient reporting of symptomatic adverse events in multicenter cancer clinical trials JAMA Oncol 3 1043 1050 2017 10.1001/jamaoncol.2016.6749 28208174 PMC5553624
46 Oken MM Creech RH Tormey DC Horton J Davis TE McFadden ET Carbone PP Toxicity and response criteria of the Eastern Cooperative Oncology Group Am J Clin Oncol 5 649 655 1982 10.1097/00000421-198212000-00014 7165009
47 Jadad AR Browman GP The WHO analgesic ladder for cancer pain management. Stepping up the quality of its evaluation JAMA 274 1870 1873 1995 10.1001/jama.1995.03530230056031 7500538
48 Pergolizzi J Böger RH Budd K Dahan A Erdine S Hans G Kress HG Langford R Likar R Raffa RB Sacerdote P Opioids and the management of chronic severe pain in the elderly: Consensus statement of an international expert panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone) Pain Pract 8 287 313 2008 10.1111/j.1533-2500.2008.00204.x 18503626
49 Canser E Martinez-Serrano B Sancho A Alonso-Babarro A Vilches Y Alonso-Yanci E Gredilla E Gilsanz F Invasive techniques for pain management in palliative care: A single center experience Pain Pract 14 632 639 2014 10.1111/papr.12115 24313989
50 van Kleef M Mekhail N van Zundert J Evidence-based guidelines for interventional pain medicine according to clinical diagnoses Pain Pract 9 247 251 2009 10.1111/j.1533-2500.2009.00297.x 19619266
51 Likar R Krainer B Sittl R Challenging the equipotency calculation for transdermal buprenorphine: Four case studies Int J Clin Pract 62 152 156 2008 10.1111/j.1742-1241.2007.01531.x 18173815
52 Cleeland CS The measurement of pain from metastatic bone disease: Capturing the patient's experience Clin Cancer Res 12 6236s 6242s 2006 10.1158/1078-0432.CCR-06-0988 17062707
53 Serlin RC Mendoza TR Nakamura Y Edwards KR Cleeland CS When is cancer pain mild, moderate or severe?. Grading pain severity by its interference with function Pain 61 277 284 1995 10.1016/0304-3959(94)00178-H 7659438
54 P F Criação da Versão Portuguesa do MOS SF-36, Parte II-Testes de validação Acta Med Port 13 119 127 2000 11026151
55 Dénommé F Kroemer M Montcuquet P Nallet G Thiery-Vuillemin A Bazan F Mouillet G Villanueva C Demarchi M Stein U Prevalence and management of pain in patients with metastatic cancer in Franche-Comté Bull Cancer 103 849 860 2016 (In French) 10.1016/j.bulcan.2016.08.007 27692731
56 van den Beuken-van Everdingen MH de Rijke JM Kessels AG Schouten HC van Kleef M Patijn J Prevalence of pain in patients with cancer: A systematic review of the past 40 years Ann Oncol 18 1437 1449 2007 10.1093/annonc/mdm056 17355955
57 Castro C Antunes L Lunet N Bento MJ Cancer incidence predictions in the North of Portugal: Keeping population-based cancer registration up to date Eur J Cancer Prev 25 472 480 2016 10.1097/CEJ.0000000000000199 26317384
58 Trama A Foschi R Larrañaga N Sant M Fuentes-Raspall R Serraino D Tavilla A Van Eycken L Nicolai N; EUROCARE-5 Working Group: Survival of male genital cancers (prostate, testis and penis) in Europe 1999–2007: Results from the EUROCARE-5 study Eur J Cancer 51 2206 2216 2015 10.1016/j.ejca.2015.07.027 26421823
59 Pina F Castro C Ferro A Bento MJ Lunet N Prostate cancer incidence and mortality in Portugal: Trends, projections and regional differences Eur J Cancer Prev 26 404 410 2017 10.1097/CEJ.0000000000000285 27483413
60 Sant M Chirlaque Lopez MD Agresti R Sánchez Pérez MJ Holleczek B Bielska-Lasota M Dimitrova N Innos K Katalinic A Langseth H Survival of women with cancers of breast and genital organs in Europe 1999–2007: Results of the EUROCARE-5 study Eur J Cancer 51 2191 2205 2015 10.1016/j.ejca.2015.07.022 26421822
61 Paice JA Portenoy R Lacchetti C Campbell T Cheville A Citron M Constine LS Cooper A Glare P Keefe F Management of chronic pain in survivors of adult cancers: American society of clinical oncology clinical practice guideline J Clin Oncol 34 3325 3345 2016 10.1200/JCO.2016.68.5206 27458286
62 Huber MB Felix J Vogelmann M Leidl R Health-related quality of life of the general german population in 2015: Results from the EQ-5D-5L Int J Environ Res Public Health 14 pii E426 2017 10.3390/ijerph14040426 28420153 PMC5409627
63 Santoro GC Carrion J Patel K Vilchez C Veith J Brodie JD Dewey SL Sex differences in regional brain glucose metabolism following opioid withdrawal and replacement Neuropsychopharmacology 42 1841 1849 2017 10.1038/npp.2017.69 28393895 PMC5520789
64 Lami MJ Martinez MP Sánchez AI Miró E Diener FN Prados G Guzmán MA Gender differences in patients with fibromyalgia undergoing cognitive-behavioral therapy for insomnia: Preliminary data Pain Pract 16 E23 E34 2016 10.1111/papr.12411 26841198
65 Suzuki N Mashu S Toyoda M Nishibori M Oral burning sensation: Prevalence and gender differences in a Japanese population Pain Pract 10 306 311 2010 10.1111/j.1533-2500.2010.00361.x 20230455
66 Kong P Yan J Liu D Ji Y Wang Y Zhuang J Wang J Hu X Yue X Skeletal-related events and overall survival of patients with bone metastasis from nonsmall cell lung cancer-A retrospective analysis Medicine (Baltimore) 96 e9327 2017 10.1097/MD.0000000000009327 29390509 PMC5758211
67 Dworkin RH Turk DC Wyrwich KW Beaton D Cleeland CS Farrar JT Haythornthwaite JA Jensen MP Kerns RD Ader DN Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations J Pain 9 105 121 2008 10.1016/j.jpain.2007.09.005 18055266
68 Zylla D Kuskowski MA Gupta K Gupta P Association of opioid requirement and cancer pain with survival in advanced non-small cell lung cancer Br J Anaesth 113 Suppl 1 i109 i116 2014 10.1093/bja/aeu351 25303989 PMC6223789
69 Zylla D Steele G Gupta P A systematic review of the impact of pain on overall survival in patients with cancer Support Care Cancer 25 1687 1698 2017 10.1007/s00520-017-3614-y 28190159