Analysis of the Clinical Management and Quality of Life of Frail Patients with Cancer and Breakthrough Pain in Clinical Practice.

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Gemma Soler González, Juan Pérez Cajaraville, Silvia Forcano Sanjuan, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-390548/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background The purpose of this study was to analyse the clinical management and quality of life of frail patients with cancer, chronic pain and breakthrough pain (BTP) and to assess whether treatment was conditioned by their frailty status. Methods This was an observational study in adult frail patients with cancer, chronic background pain and BTP. Outcomes of interest collected include clinical and sociodemographic data, Karnofsky Performance Status, quality of life (EuroQoL-5D-5L), chronic pain and BTP characteristics, as well as treatments administered for their control. Results A total of 222 patients were included with a mean age of 68 years (range 24-91), 60.5% men, with a mean Karnofsky of 63.2%. The number of daily episodes of BTP was 3.8 (95% CI 3.3-4.3), with a duration of 34.6 minutes (95% CI 28.8-40.3), and 56.8% had a gradual onset. Opioids were administered to 88.3% of patients for the chronic pain, and to 83.8% for BTP. The treatment's daily doses administered for chronic pain and BTP did not differ from those usually recommended. Quality of life was significantly worst in frail patients with cancer than no frail patients and was related to performance status (p<0.001) and to the social-familial status (p=0.045). Conclusions BTP in frail patients with cancer presents with more episodes, of a shorter duration and more gradual onset compared to other patients with BTP, and Quality of life was seriously affected. No relevant differences were seen in the doses or method of administration of treatments for chronic pain and BTP in frail patients with cancer as compared to the standard recommendations for non-frail patients. Trial registration: Not applicable to the study. Cancer Biology Oncology Cancer breakthrough pain frailty. Figures Figure 1 Figure 2 Background Frailty is defined as a physiologic state with increased vulnerability to stress factors, resulting from the decline in physiologic reserve or dysregulation of multiple physiologic systems [1]. It is a particularly important risk factor for patients with cancer because cancer itself and its treatment adds stressors that can reduce the patient’s physiologic reserve. The frequency of frailty in elderly patients with cancer is high, and approximately half of them are frail or pre-frail [2], with a greater risk of postoperative complications, chemotherapy intolerance, disease progression, and death [3-7]. Frailty has been associated in different studies with an increased risk of chemotherapy-related toxicity and poorer tolerance to treatment [8-9]. For these reasons, many studies in patients with different types of cancer now recognize the importance of the evaluation of frailty for the stratification of risk for patients in the selection of the cancer therapy and for the decision of pharmacological or non-pharmacological treatment like radiotherapy and brachytherapy [7,10-12]. Furthermore, the relationship between frailty and the prognosis of the tumour process has been widely demonstrated, and is, therefore, a factor that should be considered in these patients [13]. Therefore, the International Society of Geriatric Oncology (SIOG) recommends frailty assessment in all cancer patients over 70 years of age to help the oncologist make decisions about the most appropriate treatment for the patient [10]. Most patients with cancer suffer chronic pain, with a prevalence between 33% and 64%, reaching over 70% in patients in advanced stages of the disease [14]. Furthermore, patients with chronic pain may experience, at some point in their course, the onset of breakthrough pain (BTP), which is defined as a “transient exacerbation of pain occurring spontaneously or related to a specific predictable or unpredictable trigger, despite stable and adequately controlled background pain” [11,16]. The incidence of BTP varies across studies between 35-95% [17]. In cancer patients, the prevalence of BTP increases as the disease progresses and can reach up to 80% [14]. This frequency increases in patients with low performance status and advanced stages of the disease and is an indicator of poor prognosis [18]. Recognition of frailty status in patient with cancer conditions the decision of the type of treatment for the cancer and its dose, and it is related to its prognosis. However, in the group of frail patients with chronic pain and BTP, it is not known whether the choice of analgesic therapy is conditioned by the presence of frailty. In this regard, the objectives of this study were to analyse the clinical management and quality of life of frail patients with chronic pain and BTP and the treatments administered for pain control in standard clinical practice. Methods A cross-sectional observational study was conducted involving 29 investigators from sites in 12 Spanish provinces, including 17 medical oncology units, six pain units, three palliative care units, two geriatric departments, and one home hospitalization unit. Patients were included from 27-June-2018 to 13-May-2019. The study was approved by the Medicinal Product Research Ethics Committee of HM Hospitales de Madrid (2-April-2018; Minutes 132). Written informed consent was obtained from all patients. The study protocol was in accordance with the ethical standards described in the Declaration of Helsinki. Patient selection Patients were consecutively selected from those who attended to the clinics and who met the screening criteria, completing a single visit. No treatment was administered as a requirement of the study. The study population consisted of frail patients with a history of controlled background chronic pain and a diagnosis of BTP. Patients with cancer were analysed in this report. The Frail scale was used to identify frail patients. This is a validated scale consisting of five questions corresponding to a domain: Fatigue, Resistance, Ambulation, Illness and Weight Loss. Each domain is scored with one point. Patients were classified as frail when they scored three or more points, over five [19]. The Davies criteria and algorithm were used to diagnose BTP [16]. This algorithm determines the existence of BTP with: 1) Presence of baseline pain as persistent pain for 12 or more hours per day, in the week prior to the assessment (or that would exist if analgesics were not taken); 2) Adequately controlled background pain: no pain or mild pain (not moderate or severe) for 12 or more hours per day, during the week prior to the assessment; 3) Presence of transient pain exacerbations: severe or unbearable, with a visual analogue scale score for pain intensity greater than seven points over ten points, occurring spontaneously or related to a specific, predictable or unpredictable trigger. The inclusion criteria were: 1) Adult men and women; 2) Frail patients with ≥3 points on the Frail scale [19]; 3) Patients with controlled background pain with a visual analogue scale score for pain intensity ≤4 over ten points. 4) Diagnosis of BTP; 5) Patients who have signed the written informed consent to participate in the study. Evaluation of study objectives To assess the primary objective, the treatments received by the patient for chronic pain and BTP and their doses and administration route were recorded. Information was collected on age, sex, race, weight, height, body mass index (BMI) and occupational status. Social and family status was assessed using the Gijón scale [20,21]. It is a hetero-administered scale consisting of five variables (family situation, economic situation, housing, social relations, and social support), each with five possible categories. The categories are scored from 0 to 4 points, resulting in an overall score ranging from 0 to 20 points. The cut-off point for the detection of social risk is from 16 points on. Medical history information and the patient’s performance status (Karnofsky Performance Status) was recorded. The Karnofsky scale classifies patients into ten categories (0 and 100 points). The date of cancer diagnosis (date of diagnostic biopsy) and the organ affected by cancer were recorded. The main characteristics of background pain and BTP were recorded. Quality of life was assessed using the EuroQoL-5D-5L, a generic questionnaire consisting of five questions and a visual analogue scale with values between 0-100 millimetres (EQ-VAS). Each question has five degrees and evaluates one dimension: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression [22]. Determination of sample size The most restrictive variable for sample size determination was quality of life. The reference value for EQ-VAS in the Spanish population over 18 years of age is 75.0 points (SD 0.4) [23,24]. A sample of 222 patients would allow for the description of quality of life with a precision of 0.05 points and the power to find differences was 96% with a two-sided alpha error of 0.05 (Sample Power, IBM-SPSS). Statistical analysis A descriptive analysis was performed of frequencies and percentages for the qualitative variables, with calculation of the mean, standard deviation, minimum, maximum values, and 95% confidence intervals, for quantitative variables. Between-group comparisons were made using the Fisher test or the Chi 2 test if the variables were qualitative, and the Student’s t-test or Wilcoxon test was used for quantitative variables. A multivariate linear regression analysis was performed to explore the relationship between the EQ-VAS score and different patient characteristics: age, sex, Gijón scale score, BMI, Karnofsky Performance Status score, Frail scale score characteristics of BTP, time since diagnosis and location of cancer. Statistical significance was considered at a value of 0.05. The IBM-SPSS version 27.0 statistical package was used throughout. The STROBE guidelines (www.strobe-statement.org) were followed to present the results of cross-sectional studies [2]. Results A total of 240 patients participated in the study, with 222 patients with cancer selected for this analysis Table 1 shows their anthropometric, sociodemographic, and clinical characteristics. The percentage of patients with a Karnofsky score under 50 was 11.3% (n=25). A total of 96.8% (n=215) received treatment for some comorbidity. About 79.7% (n=177) of the patients with cancer (n=222) were receiving treatment for cancer. The median time since cancer diagnosis was 14.7 months. The chronic pain was related to the cancer in 86,5% (n=192). Chronic pain was caused by spinal problems in 5% (n=11), osteoarthritis in 2.3% (n=5), peripheral neuropathy in 1.8% (n=4), trauma in 0.5% (n=1), and other causes in 4.1% (n=9). Chronic pain was mixed in 34.7% of patients (n=77), somatic in 28.8% (n=64), visceral in 23% (n=51), and neuropathic in 13.5% (n=30). Table 2 describes the main characteristics of the BTP with no differences between patients with or without cancer. The first BTP episode was explored in 60 patients (26%) at the study visit. Frailty All patients were frail, with a mean score on the Frail scale of 3.9 points (95% CI 3.8-4). There were no significant differences in the scores per cancer location. Quality of life The mean EQ-VAS score was 51.3 mm (95% CI 48.5-54), with a median of 50 mm. Figure 1 shows the distribution of patients in the categories of the five dimensions of the quality-of-life questionnaire. No significant differences were observed in the EQ-VAS score between frail patients or according to the cancer location (Figure 2). Treatments for pain For the treatment of background pain, 27 different drugs were administered in 215 patients with a total of 316 administrations. Table 3 details the drugs used and summarizes the mean daily doses administered to patients by compound and route of administration. A total of 65.8% of the active substance administered were opioids (208/316) and they were administered to 196 patients (88.3%). The drugs used for the treatment of BTP, the doses administered, and the administration routes are described in Table 4. A total of 11 different active substances were administered in 196 patients with a total of 219 administrations of which 196 (89.5%) were opioids administered to 83.8% of patients (186/222). Factors related to Quality of life In multivariate regression analysis, the higher the Gijón social-familial evaluation scale score (plus social exclusion), the EQ-VAS quality of life score worsened in a statistically significant manner (p=0.045), so that one point higher on the Gijón scale represented a reduction in quality of life of 0.9 mm (95% CI 0.02-1.8). It was also seen that the lower the Karnofsky score, the quality-of-life score in EQ-VAS significantly worsened manner (p<0.001), so that ten points lower on the Karnofsky scale implied a 4 mm impairment in quality of life (95% CI 0.2-0.5). Discussion This observational study provides, for the first time, an overview of the clinical, social-health, and quality of life characteristics of frail patients with cancer, chronic pain and BTP together with their management in real life in Spain. It also evaluated the analgesic treatment received by patients for chronic pain and BTP and whether their choice was conditioned by the patients’ own frailty status. Characteristics of BTP in frail cancer patients have not been described previously. However, Mercadante et al. recently published a large study in 4,016 patients with cancer and BTP [26]. A comparison between our study and the latest encountered interesting results. Frail patients reported significantly greater mean number of BTP episodes per day than those in the reference study, 3.8 (95% CI 3.3-4.3) versus 2.4 (SD 1.4). The duration of BTP episodes reported by frail patients was shorter, 34.6 minutes (95% CI 28.8-40.3) versus 43.3 minutes (SD 36.9). The onset of BTP was sudden (short onset) in 43.2% of our frail patients, while this type of onset was seen in 68.9% of patients in the reference study. Even though the assessment of the BTP intensity was measured differently in both studies, we observed severe or unbearable BTP in 17.1% of our frail patients, and Mercadante et al. reported a mean intensity of 7.5 over 10 points [26]. Furthermore, in another study conducted in 1,000 cancer patients, Davies et al reported severe BTP in 62.4% of patients. Similar results were observed among frail patients (62.6%) in our study [27]. Predictable BTP was found in 35.1% of our frail patients, alike data (30.5%) described by Mercadante et al. 30 Difference on BTP mechanism was observed in both populations. Neuropathic pain was more frequently observed among our frail patients (16.7% vs 8.1%), while mixed pain was more common in those cancer patients of the referred study (71.8%, vs 31.1%) [26]. The higher the number of BTP episodes, the shorter the duration and the more gradual onset seen in frail patients. A pathophysiological process related to frailty status might underly these observations since a greater frequency of BTP episodes has been reported in patients with worse performance status [27]. Interestingly, the performance status of patients observed in both studies was similar, 63.2 (95% CI 61-65.4) versus 61.8 (SD 18.73) [26]. Among our frail patients, 79.7% of them were in active treatment for cancer, likewise 78% of patients in the reference study. This situation should be considered, since receiving this type of treatment could condition the administration of other treatments, such as, for example, for background pain and BTP [26]. Drugs for the treatment of chronic pain and BTP administrated to frail patients did not substantially differ on their doses and the frequency of administration (Tables 3 and 4), to the standard treatment for chronic pain. Regarding BTP treatment, in our study, 83.8% of frail patients with cancer received opioid treatment for BTP control, just as patients with cancer included in other studies [26,27]. Transmucosal immediate release fentanyl was administered to 68.5% of frail patients with cancer, the treatment of choice for BTP in cancer patients [14]. The doses of the treatments were within the range recommended in their prescribing information. On the other hand, our attention was caught by the fact that 10 patients used drugs that are not usually indicated for BTP but for basal pain therapy in standard practice, such as dexketoprofen, ibuprofen, metamizole or paracetamol, frequently complementary to the opioids administrated for the background chronic pain. In the Table 4 the number of administrations for such treatments were 28, but only 6 patients received only these drugs. We observed BTP interference with daily activities in 93.7% of frail patients (Figure 1) while Mercadante et al reported that in 86% of their patients [32]. Furthermore, they found that age, Karnofsky, BTP severity, short onset, and longer duration of BTP significantly interfered with daily activities of cancer patients. In our study, we were able to relate a poorer quality of life score (EQ-VAS) to a worse Karnofsky score in frail patients, already described in different studies [26,28,29]. In addition, our study found a significant association between quality of life and social exclusion in frail patients with cancer but due to the cross-sectional design we cannot know which one was the first event. The EuroQoL-5D-5L questionnaire conducted in healthy Spanish population revealed that the 65–74-year-old age group reported problems with mobility (29.3%), self-care (10.4%), daily activities (19.1%), pain (43%), and anxiety or depression (20%) [30]. According to our study, frail cancer patients with BTP seem to be more impaired, as 93.2% of frail patients experienced greater mobility problems, 74.2% self-care problems, 93.7% problems with activities of daily living, 98.2% pain, and 81.4% anxiety or depression (Figure 1). Meanwhile, data observed in a review of 32 studies in patients with cancer shows impairment rates for mobility ranging from 2-60%, self-care 2-50%, daily activities 15-100%, pain 12-80%, and anxiety or depression 13-100%, i.e., there is greater deterioration in frail patients in our study in three of the five dimensions [31]. The mean EQ-VAS score, as a measure of patient-perceived quality of life, was 51.3 mm (95% CI 48.5-54) in frail patients with BTP in our study, values well below those seen in the general Spanish population of the same age group, 69 mm (Figure 2) [23]. In addition, this value is much more affected than in cancer patients, analysed in a review of 32 studies, who presented a value of 68.6 mm [31]. It is known that the occurrence of BTP has a significant impact on patient quality of life [32]. In the case of patients in our study, the low quality of life levels observed could be due to both BTP and frailty status, or to the interaction of both factors. In Spain, the prevalence of frailty has been studied in six cohort studies, ranging from 2.4% to 27.3% in patients over 65 years of age [24]. However, in the setting of our study, conducted mainly in medical oncology units and in some pain and geriatric units, the prevalence of frailty is much higher [7,10,13], so the results of this study are relevant to standard clinical practice in these units. This study has several limitations inherent to the cross-sectional observational design, which prevents causal relationships from being established. Patients were classified as frail using the Frail scale [19], following national recommendations [24], so frail patients could be classified differently from other classification scales not based on the Fried criteria [1]. As this is a cross-sectional study, patients were included at different follow-up times after the onset of BTP. For this reason, we could not analyse which were the first treatments for BTP in frail patients or their doses, which could differ at the start, and then be adjusted. Other treatments for patients with cancer such radiotherapy and brachytherapy play an important role in this setting of patients for the treatment of pain with many advantages in elderly and frail patients, but not collected in our study that was focused on pharmacological treatment [11,12] Conclusions This study concluded that some characteristics of BTP in frail patients with cancer differ from those reported in other studies. In addition, it has been seen that the treatments used for both chronic pain and BTP in frail patients are like those commonly prescribed in non-frail patients. Quality of life in frail patients has also been found to be severely impaired as compared to the population of patients with cancer and was related to a poorer performance status of the patient and poorer social-familial status. This relationship between frailty and impaired quality of life highlights the importance of the frailty assessment in all patients with BTP. Abbreviations BMI: Body mass index BTP: Breakthrough pain CI: Confidence Interval EQ-VAS: Visual analogue scale of the EuroQoL-5D-5L Quality of life questionnaire QoL: Quality of life SD: Standard deviation SIOG: International Society of Geriatric Oncology Declarations Ethics approval and consent to participate The study was approved by the Medicinal Product Research Ethics Committee of HM Hospitales de Madrid (2-April-2018; Minutes 132). Written informed consent was obtained from all patients. The study protocol was in accordance with the ethical standards described in the Declaration of Helsinki, and all participants’ privacy rights were respected. Consent for publication Not applicable. Availability of data and material The study data is available upon reasonable request to the corresponding author. Competing interest GSG, JPC and SFS received payment from Kyowa Kirin Farmacéutica, S.L. for their participation in the design and coordination of the study. AJJL, ACA and IHG are employees at Kyowa Kirin Farmacéutica, S.L. BSL was contracted by Kyowa Kirin Farmacéutica, S.L. for project management. The rest of the authors declare that they have no conflicts of interest with the study results. Funding The study was sponsored by Kyowa Kirin Farmacéutica, S.L. The sponsor was involved in the design of the study and the decision to submit the manuscript for publication. Author's contributions GSG, JPC, SFS, contributed to the study concepts, the study design, data acquisition and manuscript review. AJJL, ACA and IHG contributed to the study concepts and design and the manuscript review. BSL contributed to the study design, quality control of data, statistical analysis, and manuscript preparation. All authors have read and approved the manuscript. Acknowledgements We would like to thank the participating patients for their collaboration in the study. We acknowledge the involvement of the following investigators: Ruth Afonso Gómez; Javier Arranz Durán; Juan Antonio Avellana Zaragoza; Enrique Cabrera Espinós; José Ignacio Calvo Sáez; Victoria Casado Echarren; Mayte Delgado Ureña; Isabela Díaz de Corcuera Frutos; José Antonio Díaz Ricós; Rosa Delia García Marrero; Plácido Guardia Mancilla; Oliver Higuera Gómez; Anastasi Martín Pérez; Belinda Montalbán Moreno; Juan Antonio Núñez Sobrino; Amparo Oltra Ferrando; María Gorety Pazos González; Paola Pimentel Cáceres; Andrea Marisol Sánchez; Gloria Mª Serrano Montero; Lucía Teijeira Sánchez; Albert Tuca Rodríguez; Miguel Ángel Vilar Rodríguez References Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. 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Impact of cancer on Health Related Quality of Life: Evidence using the EQ-5D. Barcelona 2006 EuroQol Proceedings, 26-08-2006. https://euroqol.org/search-for-eq-5d-publications/ [accessed 12 February 2021]. Fortner BV, Okon TA, Portenoy RK. A survey of pain-related hospitalizations, emergency department visits, and physician office visits reported by cancer patients with and without history of breakthrough pain. J Pain 2002; 3: 38-44. https://doi.org/10.1054/jpai.2002.27136. Tables Table 1. Sociodemographic and clinical data of frail patients with cancer and breakthrough pain. Sociodemographic or clinical variable (n=222) % (n) or mean (95% CI) Age 68.2 (66.6-69.8) Gender Male 135 (60.8) Female 39.2 (87) Race Caucasian 80.2 (178) Hispanic 19.4 (43) Black 0.4 (1) Employment status Employee 2.3 (5) Temporary work disability 12.6 (28) Permanent work disability 15.8 (35) Retirees 69.3 (154) Gijón Scale Overall score (0-20) 4.9 (4.5-5.3) No social-familial risk (<16) 99.6 (221) With social-familial risk (≥16) 0.4 (1) Body Mass Index (kg/m 2 ) 25.1 (24.2-25.7) Classification according to body mass index (BMI) (n=229) Cachexic (BMI =20 and =25 and =30 kg/m 2 ) 16.6 (37) Karnofsky performance status 63.2 (61-65.4) Time since cancer diagnosis (months) 33.9 (27.3-40.5) Primary cancer location Lung 33 (73) Gastrointestinal 23.5 (52) Breast 7.2 (16) Prostate 5 (11) Other 31.5 (70) Table 2. Characteristics of breakthrough pain in frail patients with cancer. Characteristics of breakthrough pain (n= 222) % (n) or mean (95% CI) Number of daily episodes 3.8 (3.3-4.3) Duration of episodes (minutes) 34.6 (28.8-40.3) Location Lumbar 30.2 (67) Abdomen 22.5 (50) Chest 21.2 (47) Head 11.7 (26) Other 14.4 (32) Onset Gradual 56.8 (126) Sudden 43.2 (96) Intensity Mild 3.2 (7) Moderate 34.2 (76) Severe 45.5 (101) Unbearable 17.1 (38) Incidental No 52.5 (116) Yes 47.5 (105) Predictable No 64.9 (144) Yes 35.1 (78) Time of day when it appears At night 12.6 (28) During the day 36.9 (82) Unrelated 50.5 (112) Type of pain Somatic 27.5 (61) Visceral 24.8 (55) Neuropathic 16.7 (37) Mixed 31.1 (69) Table 3. Drugs administered to frail patients with cancer and breakthrough pain for the treatment of chronic pain. Active ingredient for chronic pain Administration route Daily frequency Daily dose N a Mean Aceclofenac Oral Every 12 h 1 200 mg Amitriptyline Oral Every 24 h 1 10 mg Baclofen Oral Every 24 h 1 10 mg Butylscopolamine Parenteral Every 6 h 1 40 mg Buprenorphine Topical/Transdermal Every 72 h 2 36.8 μg Clonazepam Oral Every 8 h 1 1.5 mg Dexketoprofen Oral Every 12 h 1 50 mg Every 8 h 3 75 mg Parenteral Every 8 h 1 75 mg Dexamethasone Oral Every 24 h 11 3.4 mg Every 12 h 1 8 mg Every 8 h 1 12 mg Parenteral Every 24 h 1 12 mg Every 8 h 2 12 mg Duloxetine Oral Every 24 h 2 45 mg Eslicarbazepine Oral Every 24 h 1 800 mg Etoricoxib Oral Every 24 h 2 90 mg Fentanyl Respiratory/inhaled Every 8 h 1 300 μg Every 3 h 1 500 μg Topical/Transdermal Every 24 h 37 65.5 μg On demand 10 56.3 μg Every 48 h 1 50 μg Every 72 h 64 14.6 μg Gabapentin Oral Every 24 h 1 600 mg Every 8 h 7 1200 mg Ibuprofen Oral Every 8 h 1 1800 mg Lacosamide Oral Every 12 h 1 200 mg Methadone Oral Every 8 h 1 15 mg Metamizole Oral Every 12 h 1 0.8 mg Every 8 h 18 1826 mg Parenteral Every 8 h 3 6 mg Morphine Oral Every 24 h 2 65 mg Every 12 h 31 85.5 mg Every 8 h 5 486 mg Parenteral Every 24 h 6 108.5 mg On demand 2 55 mg Naproxen Oral Every 12 h 2 700 mg Oxycodone Oral Every 12 h 5 68 mg Every 8 h 2 22.5 mg Every 6 h 1 20 mg Oxycodone/Naloxone Oral Every 24 h 2 6.3 mg Every 12 h 12 42.5 mg Every 8 h 1 90 mg Paracetamol Oral Every 8 h 20 2797 mg Every 3 h 1 5000 mg Parenteral Every 8 h 5 2400 mg Paracetamol/codeine Oral Every 8 h 1 3000 mg Prednisone Oral Every 24 h 1 5 mg Pregabalin Oral Every 24 h 4 43.8 mg Every 12 h 10 160 mg Every 8 h 1 75 mg Tapentadol Oral Every 24 h 2 150 mg Every 12 h 10 155 mg Tramadol Oral Every 12 h 1 150 mg Every 8 h 6 156 mg Every 6 h 1 400 mg Parenteral Every 12 h 1 200 mg Tramadol/paracetamol Oral Every 8 h 1 225 mg a. N: number of patients with the treatment, patients received one or more treatments. Table 4. Drugs administered to frail patients with cancer for the treatment of breakthrough pain. Active ingredient for breakthrough pain Route Unit dose Unit dose in the Mercadante study[26] N a Mean (95% CI) Mean dose (SD) Dexketoprofen Oral 2 25 mg - - Duloxetine Oral 1 30 mg - - Fentanyl Oral 8 190 μg (71.1-309) 234.6 (183.1) μg Sublingual 81 161.7 μg (139-184) 231.4 (171.1) μg Nasal with pectin 59 155.9 μg (130-182) 167.7 (125.7) μg Nasal without pectin 1 100 μg - 100 (50.7) μg Transdermal 3 29 μg (-19-77) - Ibuprofen Oral 1 400 mg - - Metamizole Oral 5 231.2 mg (-159-621) - Parenteral 4 2 mg (2-2) - Metamizole/ Scopolamine Parenteral 1 2500/20 mg - - Morphine Oral 12 11.7 mg (8-15) 11.8 (8.2) mg Parenteral 17 10.7 mg (7-14) 8.2 (6.1) mg Oxycodone Oral 6 9.2 mg (-2-20) - Oxycodone/Naloxone Oral 1 10 mg - - Paracetamol Oral 6 683.3 mg (288-1078) - Parenteral 3 1000 mg (1000-1000) - Tramadol Oral 6 54.2 mg (44-65) - a. N: number of patients with the treatment. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-390548","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":19739401,"identity":"c916975f-4976-4975-8c8f-1dd4d0f0d714","order_by":0,"name":"Gemma Soler González","email":"","orcid":"","institution":"Instituto Catalá d'Oncología L`Hospitalet, Medical Oncology Department, Hospitalet de Llobregat, Barcelona","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gemma","middleName":"Soler","lastName":"González","suffix":""},{"id":19739402,"identity":"96e9034d-9224-4818-b154-d4a1d383e382","order_by":1,"name":"Juan Pérez Cajaraville","email":"","orcid":"","institution":"Hospital Universitario HM Puerta del Sur, Pain Unit, Madrid","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Juan","middleName":"Pérez","lastName":"Cajaraville","suffix":""},{"id":19739403,"identity":"371b0e71-45de-453d-bea3-a635603ed794","order_by":2,"name":"Silvia Forcano Sanjuan","email":"","orcid":"","institution":"Hopital Univeritario y Politécnico La Fe, Geriatric Department, Valencia","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Silvia","middleName":"Forcano","lastName":"Sanjuan","suffix":""},{"id":19739404,"identity":"ee3a73be-ec6b-4b7b-9a83-518506b78145","order_by":3,"name":"José Luis Firvida 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Alicante","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Natividad","middleName":"Martínez","lastName":"Banaclocha","suffix":""},{"id":19739407,"identity":"b4aaeff4-589d-40f6-939d-87c01c1ada5a","order_by":6,"name":"Antonio Javier Jiménez López","email":"","orcid":"","institution":"Kyowa Kirin Farmacéutica, S.L., Medical Department, Madrid","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"Javier Jiménez","lastName":"López","suffix":""},{"id":19739408,"identity":"43b88539-33e7-48c9-8ed0-69e2c8f44c69","order_by":7,"name":"Ana Cabezón Álvarez","email":"","orcid":"","institution":"Kyowa Kirin Farmacéutica, S.L., Medical Department, Madrid","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ana","middleName":"Cabezón","lastName":"Álvarez","suffix":""},{"id":19739409,"identity":"6b0605ec-5b8d-449d-9cf1-cac97c8fa6a0","order_by":8,"name":"Ibone Huerta 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S.L.","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Begoña","middleName":"","lastName":"Soler-López","suffix":""}],"badges":[],"createdAt":"2021-04-03 22:45:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-390548/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-390548/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":7667863,"identity":"394bd649-5a24-479d-9c97-12598a03c86b","added_by":"auto","created_at":"2021-04-05 14:30:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":28394,"visible":true,"origin":"","legend":"Distribution of patients in the categories of the five dimensions of the EuroQoL-5D-5L health-related quality of life questionnaire in frail patients with cancer and breakthrough pain.","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-390548/v1/f5da712c8b205c5596a3ad71.png"},{"id":7667864,"identity":"2b718e24-dce3-477f-8118-462db3780dde","added_by":"auto","created_at":"2021-04-05 14:30:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":31622,"visible":true,"origin":"","legend":"Mean score of the quality-of-life EQ-VAS in frail patients with cancer and breakthrough pain. Comparison by cancer location and with the general healthy population for the same age group.\n\n__ __ __Mean EQ-VAS score in the general healthy population of the 65-74 years-old age group [30].\n_ _ _ _ _ Mean EQ-VAS score for patients with cancer [31].\nEQ-VAS: EuroQoL-5D-5L health-related quality of life questionnaire visual analogue scale; Value 0 means worst quality of life and value 100 means the best quality of life\n","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-390548/v1/a3e573492cba2ff2ecc366b7.png"},{"id":13683920,"identity":"5240cdbb-3b4e-4da2-bd83-e8f9919e542c","added_by":"auto","created_at":"2021-09-17 12:05:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":612723,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-390548/v1/57e12cb0-4d8f-46eb-9b98-dd194fe15ff1.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eAnalysis of the Clinical Management and Quality of Life of Frail Patients with Cancer and Breakthrough Pain in Clinical Practice.\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eFrailty is defined as a physiologic state with increased vulnerability to stress factors, resulting from the decline in physiologic reserve or dysregulation of multiple physiologic systems [1]. It is a particularly important risk factor for patients with cancer because cancer itself and its treatment adds stressors that can reduce the patient\u0026rsquo;s physiologic reserve. The frequency of frailty in elderly patients with cancer is high, and approximately half of them are frail or pre-frail [2], with a greater risk of postoperative complications, chemotherapy intolerance, disease progression, and death [3-7]. Frailty has been associated in different studies with an increased risk of chemotherapy-related toxicity and poorer tolerance to treatment [8-9]. For these reasons, many studies in patients with different types of cancer now recognize the importance of the evaluation of frailty for the stratification of risk for patients in the selection of the cancer therapy and for the decision of pharmacological or non-pharmacological treatment like radiotherapy and brachytherapy [7,10-12]. Furthermore, the relationship between frailty and the prognosis of the tumour process has been widely demonstrated, and is, therefore, a factor that should be considered in these patients [13]. Therefore, the International Society of Geriatric Oncology (SIOG) recommends frailty assessment in all cancer patients over 70 years of age to help the oncologist make decisions about the most appropriate treatment for the patient [10].\u003c/p\u003e\n\u003cp\u003eMost patients with cancer suffer chronic pain, with a prevalence between 33% and 64%, reaching over 70% in patients in advanced stages of the disease [14]. Furthermore, patients with chronic pain may experience, at some point in their course, the onset of breakthrough pain (BTP), which is defined as a \u0026ldquo;transient exacerbation of pain occurring spontaneously or related to a specific predictable or unpredictable trigger, despite stable and adequately controlled background pain\u0026rdquo; [11,16].\u003c/p\u003e\n\u003cp\u003eThe incidence of BTP varies across studies between 35-95% [17]. In cancer patients, the prevalence of BTP increases as the disease progresses and can reach up to 80% [14]. This frequency increases in patients with low performance status and advanced stages of the disease and is an indicator of poor prognosis [18].\u003c/p\u003e\n\u003cp\u003eRecognition of frailty status in patient with cancer conditions the decision of the type of treatment for the cancer and its dose, and it is related to its prognosis. However, in the group of frail patients with chronic pain and BTP, it is not known whether the choice of analgesic therapy is conditioned by the presence of frailty. In this regard, the objectives of this study were to analyse the clinical management and quality of life of frail patients with chronic pain and BTP and the treatments administered for pain control in standard clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA cross-sectional observational study was conducted involving 29 investigators from sites in 12 Spanish provinces, including 17 medical oncology units, six pain units, three palliative care units, two geriatric departments, and one home hospitalization unit.\u003c/p\u003e\n\u003cp\u003ePatients were included from 27-June-2018 to 13-May-2019. The study was approved by the Medicinal Product Research Ethics Committee of HM Hospitales de Madrid (2-April-2018; Minutes 132).\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all patients. The study protocol was in accordance with the ethical standards described in the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatient selection\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were consecutively selected from those who attended to the clinics and who met the screening criteria, completing a single visit. No treatment was administered as a requirement of the study.\u003c/p\u003e\n\u003cp\u003eThe study population consisted of frail patients with a history of controlled background chronic pain and a diagnosis of BTP. Patients with cancer were analysed in this report.\u003c/p\u003e\n\u003cp\u003eThe Frail scale was used to identify frail patients. This is a validated scale consisting of five questions corresponding to a domain: Fatigue, Resistance, Ambulation, Illness and Weight Loss. Each domain is scored with one point. Patients were classified as frail when they scored three or more points, over five [19].\u003c/p\u003e\n\u003cp\u003eThe Davies criteria and algorithm were used to diagnose BTP [16]. This algorithm determines the existence of BTP with: 1) Presence of baseline pain as persistent pain for 12 or more hours per day, in the week prior to the assessment (or that would exist if analgesics were not taken); 2) Adequately controlled background pain: no pain or mild pain (not moderate or severe) for 12 or more hours per day, during the week prior to the assessment; 3) Presence of transient pain exacerbations: severe or unbearable, with a visual analogue scale score for pain intensity greater than seven points over ten points, occurring spontaneously or related to a specific, predictable or unpredictable trigger.\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria were: 1) Adult men and women; 2) Frail patients with \u0026ge;3 points on the Frail scale [19]; 3) Patients with controlled background pain with a visual analogue scale score for pain intensity \u0026le;4 over ten points. 4) Diagnosis of BTP; 5) Patients who have signed the written informed consent to participate in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEvaluation of study objectives\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo assess the primary objective, the treatments received by the patient for chronic pain and BTP and their doses and administration route were recorded.\u003c/p\u003e\n\u003cp\u003eInformation was collected on age, sex, race, weight, height, body mass index (BMI) and occupational status.\u003c/p\u003e\n\u003cp\u003eSocial and family status was assessed using the Gij\u0026oacute;n scale [20,21]. It is a hetero-administered scale consisting of five variables (family situation, economic situation, housing, social relations, and social support), each with five possible categories. The categories are scored from 0 to 4 points, resulting in an overall score ranging from 0 to 20 points. The cut-off point for the detection of social risk is from 16 points on.\u003c/p\u003e\n\u003cp\u003eMedical history information and the patient\u0026rsquo;s performance status (Karnofsky Performance Status) was recorded. The Karnofsky scale classifies patients into ten categories (0 and 100 points).\u003c/p\u003e\n\u003cp\u003eThe date of cancer diagnosis (date of diagnostic biopsy) and the organ affected by cancer were recorded.\u003c/p\u003e\n\u003cp\u003eThe main characteristics of background pain and BTP were recorded.\u003c/p\u003e\n\u003cp\u003eQuality of life was assessed using the EuroQoL-5D-5L, a generic questionnaire consisting of five questions and a visual analogue scale with values between 0-100 millimetres (EQ-VAS). Each question has five degrees and evaluates one dimension: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression [22].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDetermination of sample size\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe most restrictive variable for sample size determination was quality of life. The reference value for EQ-VAS in the Spanish population over 18 years of age is 75.0 points (SD 0.4) [23,24]. A sample of 222 patients would allow for the description of quality of life with a precision of 0.05 points and the power to find differences was 96% with a two-sided alpha error of 0.05 (Sample Power, IBM-SPSS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA descriptive analysis was performed of frequencies and percentages for the qualitative variables, with calculation of the mean, standard deviation, minimum, maximum values, and 95% confidence intervals, for quantitative variables.\u003c/p\u003e\n\u003cp\u003eBetween-group comparisons were made using the Fisher test or the Chi\u003csup\u003e2\u003c/sup\u003e test if the variables were qualitative, and the Student\u0026rsquo;s t-test or Wilcoxon test was used for quantitative variables.\u003c/p\u003e\n\u003cp\u003eA multivariate linear regression analysis was performed to explore the relationship between the EQ-VAS score and different patient characteristics: age, sex, Gij\u0026oacute;n scale score, BMI, Karnofsky Performance Status score, Frail scale score characteristics of BTP, time since diagnosis and location of cancer. Statistical significance was considered at a value of 0.05. The IBM-SPSS version 27.0 statistical package was used throughout. The STROBE guidelines (www.strobe-statement.org) were followed to present the results of cross-sectional studies [2].\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 240 patients participated in the study, with 222 patients with cancer selected for this analysis Table 1 shows their anthropometric, sociodemographic, and clinical characteristics. The percentage of patients with a Karnofsky score under 50 was 11.3% (n=25).\u003c/p\u003e\n\u003cp\u003eA total of 96.8% (n=215) received treatment for some comorbidity. About 79.7% (n=177) of the patients with cancer (n=222) were receiving treatment for cancer. The median time since cancer diagnosis was 14.7 months.\u003c/p\u003e\n\u003cp\u003eThe chronic pain was related to the cancer in 86,5% (n=192). Chronic pain was caused by spinal problems in 5% (n=11), osteoarthritis in 2.3% (n=5), peripheral neuropathy in 1.8% (n=4), trauma in 0.5% (n=1), and other causes in 4.1% (n=9). Chronic pain was mixed in 34.7% of patients (n=77), somatic in 28.8% (n=64), visceral in 23% (n=51), and neuropathic in 13.5% (n=30).\u003c/p\u003e\n\u003cp\u003eTable 2 describes the main characteristics of the BTP with no differences between patients with or without cancer. The first BTP episode was explored in 60 patients (26%) at the study visit.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFrailty\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients were frail, with a mean score on the Frail scale of 3.9 points (95% CI 3.8-4). There were no significant differences in the scores per cancer location.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eQuality of life \u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mean EQ-VAS score was 51.3 mm (95% CI 48.5-54), with a median of 50 mm. Figure 1 shows the distribution of patients in the categories of the five dimensions of the quality-of-life questionnaire. No significant differences were observed in the EQ-VAS score between frail patients or according to the cancer location (Figure 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTreatments for pain\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the treatment of background pain, 27 different drugs were administered in 215 patients with a total of 316 administrations. Table 3 details the drugs used and summarizes the mean daily doses administered to patients by compound and route of administration. A total of 65.8% of the active substance administered were opioids (208/316) and they were administered to 196 patients (88.3%).\u003c/p\u003e\n\u003cp\u003eThe drugs used for the treatment of BTP, the doses administered, and the administration routes are described in Table 4. A total of 11 different active substances were administered in 196 patients with a total of 219 administrations of which 196 (89.5%) were opioids administered to 83.8% of patients (186/222).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFactors related to Quality of life \u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn multivariate regression analysis, the higher the Gij\u0026oacute;n social-familial evaluation scale score (plus social exclusion), the EQ-VAS quality of life score worsened in a statistically significant manner (p=0.045), so that one point higher on the Gij\u0026oacute;n scale represented a reduction in quality of life of 0.9 mm (95% CI 0.02-1.8). It was also seen that the lower the Karnofsky score, the quality-of-life score in EQ-VAS significantly worsened manner (p\u0026lt;0.001), so that ten points lower on the Karnofsky scale implied a 4 mm impairment in quality of life (95% CI 0.2-0.5).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis observational study provides, for the first time, an overview of the clinical, social-health, and quality of life characteristics of frail patients with cancer, chronic pain and BTP together with their management in real life in Spain. It also evaluated the analgesic treatment received by patients for chronic pain and BTP and whether their choice was conditioned by the patients\u0026rsquo; own frailty status.\u003c/p\u003e\n\u003cp\u003eCharacteristics of BTP in frail cancer patients have not been described previously. However, Mercadante et al. recently published a large study in 4,016 patients with cancer and BTP [26]. A comparison between our study and the latest encountered interesting results. Frail patients reported significantly greater mean number of BTP episodes per day than those in the reference study, 3.8 (95% CI 3.3-4.3) versus 2.4 (SD 1.4). The duration of BTP episodes reported by frail patients was shorter, 34.6 minutes (95% CI 28.8-40.3) versus 43.3 minutes (SD 36.9). The onset of BTP was sudden (short onset) in 43.2% of our frail patients, while this type of onset was seen in 68.9% of patients in the reference study. Even though the assessment of the BTP intensity was measured differently in both studies, we observed severe or unbearable BTP in 17.1% of our frail patients, and Mercadante et al. reported a mean intensity of 7.5 over 10 points [26]. Furthermore, in another study conducted in 1,000 cancer patients, Davies et al reported severe BTP in 62.4% of patients. Similar results were observed among frail patients (62.6%) in our study [27].\u003c/p\u003e\n\u003cp\u003ePredictable BTP was found in 35.1% of our frail patients, alike data (30.5%) described by Mercadante et al.\u003csup\u003e30\u003c/sup\u003e Difference on BTP mechanism was observed in both populations. Neuropathic pain was more frequently observed among our frail patients (16.7% vs 8.1%), while mixed pain was more common in those cancer patients of the referred study (71.8%, vs 31.1%) [26].\u003c/p\u003e\n\u003cp\u003eThe higher the number of BTP episodes, the shorter the duration and the more gradual onset seen in frail patients. A pathophysiological process related to frailty status might underly these observations since a greater frequency of BTP episodes has been reported in patients with worse performance status [27]. Interestingly, the performance status of patients observed in both studies was similar, 63.2 (95% CI 61-65.4) versus 61.8 (SD 18.73) [26].\u003c/p\u003e\n\u003cp\u003eAmong our frail patients, 79.7% of them were in active treatment for cancer, likewise 78% of patients in the reference study. This situation should be considered, since receiving this type of treatment could condition the administration of other treatments, such as, for example, for background pain and BTP [26].\u003c/p\u003e\n\u003cp\u003eDrugs for the treatment of chronic pain and BTP administrated to frail patients did not substantially differ on their doses and the frequency of administration (Tables 3 and 4), to the standard treatment for chronic pain. Regarding BTP treatment, in our study, 83.8% of frail patients with cancer received opioid treatment for BTP control, just as patients with cancer included in other studies [26,27]. Transmucosal immediate release fentanyl was administered to 68.5% of frail patients with cancer, the treatment of choice for BTP in cancer patients [14]. The doses of the treatments were within the range recommended in their prescribing information. On the other hand, our attention was caught by the fact that 10 patients used drugs that are not usually indicated for BTP but for basal pain therapy in standard practice, such as dexketoprofen, ibuprofen, metamizole or paracetamol, frequently complementary to the opioids administrated for the background chronic pain. In the Table 4 the number of administrations for such treatments were 28, but only 6 patients received only these drugs.\u003c/p\u003e\n\u003cp\u003eWe observed BTP interference with daily activities in 93.7% of frail patients (Figure 1) while Mercadante et al reported that in 86% of their patients [32]. Furthermore, they found that age, Karnofsky, BTP severity, short onset, and longer duration of BTP significantly interfered with daily activities of cancer patients. In our study, we were able to relate a poorer quality of life score (EQ-VAS) to a worse Karnofsky score in frail patients, already described in different studies [26,28,29]. In addition, our study found a significant association between quality of life and social exclusion in frail patients with cancer but due to the cross-sectional design we cannot know which one was the first event.\u003c/p\u003e\n\u003cp\u003eThe EuroQoL-5D-5L questionnaire conducted in healthy Spanish population revealed that the 65\u0026ndash;74-year-old age group reported problems with mobility (29.3%), self-care (10.4%), daily activities (19.1%), pain (43%), and anxiety or depression (20%) [30]. According to our study, frail cancer patients with BTP seem to be more impaired, as 93.2% of frail patients experienced greater mobility problems, 74.2% self-care problems, 93.7% problems with activities of daily living, 98.2% pain, and 81.4% anxiety or depression (Figure 1). Meanwhile, data observed in a review of 32 studies in patients with cancer shows impairment rates for mobility ranging from 2-60%, self-care 2-50%, daily activities 15-100%, pain 12-80%, and anxiety or depression 13-100%, i.e., there is greater deterioration in frail patients in our study in three of the five dimensions [31].\u003c/p\u003e\n\u003cp\u003eThe mean EQ-VAS score, as a measure of patient-perceived quality of life, was 51.3 mm (95% CI 48.5-54) in frail patients with BTP in our study, values well below those seen in the general Spanish population of the same age group, 69 mm (Figure 2) [23]. In addition, this value is much more affected than in cancer patients, analysed in a review of 32 studies, who presented a value of 68.6 mm [31].\u003c/p\u003e\n\u003cp\u003eIt is known that the occurrence of BTP has a significant impact on patient quality of life [32]. In the case of patients in our study, the low quality of life levels observed could be due to both BTP and frailty status, or to the interaction of both factors.\u003c/p\u003e\n\u003cp\u003eIn Spain, the prevalence of frailty has been studied in six cohort studies, ranging from 2.4% to 27.3% in patients over 65 years of age [24]. However, in the setting of our study, conducted mainly in medical oncology units and in some pain and geriatric units, the prevalence of frailty is much higher [7,10,13], so the results of this study are relevant to standard clinical practice in these units.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations inherent to the cross-sectional observational design, which prevents causal relationships from being established. Patients were classified as frail using the Frail scale [19], following national recommendations [24], so frail patients could be classified differently from other classification scales not based on the Fried criteria [1]. As this is a cross-sectional study, patients were included at different follow-up times after the onset of BTP. For this reason, we could not analyse which were the first treatments for BTP in frail patients or their doses, which could differ at the start, and then be adjusted. Other treatments for patients with cancer such radiotherapy and brachytherapy play an important role in this setting of patients for the treatment of pain with many advantages in elderly and frail patients, but not collected in our study that was focused on pharmacological treatment [11,12]\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study concluded that some characteristics of BTP in frail patients with cancer differ from those reported in other studies. In addition, it has been seen that the treatments used for both chronic pain and BTP in frail patients are like those commonly prescribed in non-frail patients. Quality of life in frail patients has also been found to be severely impaired as compared to the population of patients with cancer and was related to a poorer performance status of the patient and poorer social-familial status. This relationship between frailty and impaired quality of life highlights the importance of the frailty assessment in all patients with BTP.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBMI: Body mass index\u003c/p\u003e\n\u003cp\u003eBTP: Breakthrough pain\u003c/p\u003e\n\u003cp\u003eCI: Confidence Interval\u003c/p\u003e\n\u003cp\u003eEQ-VAS: Visual analogue scale of the EuroQoL-5D-5L Quality of life questionnaire\u003c/p\u003e\n\u003cp\u003eQoL: Quality of life\u003c/p\u003e\n\u003cp\u003eSD: Standard deviation\u003c/p\u003e\n\u003cp\u003eSIOG: International Society of Geriatric Oncology\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Medicinal Product Research Ethics Committee of HM Hospitales de Madrid (2-April-2018; Minutes 132).\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all patients. The study protocol was in accordance with the ethical standards described in the Declaration of Helsinki, and all participants\u0026rsquo; privacy rights were respected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study data is available upon reasonable request to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGSG, JPC and SFS received payment from Kyowa Kirin Farmac\u0026eacute;utica, S.L. for their participation in the design and coordination of the study. AJJL, ACA and IHG are employees at Kyowa Kirin Farmac\u0026eacute;utica, S.L. BSL was contracted by Kyowa Kirin Farmac\u0026eacute;utica, S.L. for project management. The rest of the authors declare that they have no conflicts of interest with the study results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was sponsored by Kyowa Kirin Farmac\u0026eacute;utica, S.L. The sponsor was involved in the design of the study and the decision to submit the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor's contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGSG, JPC, SFS, contributed to the study concepts, the study design, data acquisition and manuscript review. AJJL, ACA and IHG contributed to the study concepts and design and the manuscript review. BSL contributed to the study design, quality control of data, statistical analysis, and manuscript preparation.\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the participating patients for their collaboration in the study.\u003c/p\u003e\n\u003cp\u003eWe acknowledge the involvement of the following investigators: Ruth Afonso G\u0026oacute;mez; Javier Arranz Dur\u0026aacute;n; Juan Antonio Avellana Zaragoza; Enrique Cabrera Espin\u0026oacute;s; Jos\u0026eacute; Ignacio Calvo S\u0026aacute;ez; Victoria Casado Echarren; Mayte Delgado Ure\u0026ntilde;a; Isabela D\u0026iacute;az de Corcuera Frutos; Jos\u0026eacute; Antonio D\u0026iacute;az Ric\u0026oacute;s; Rosa Delia Garc\u0026iacute;a Marrero; Pl\u0026aacute;cido Guardia Mancilla; Oliver Higuera G\u0026oacute;mez; Anastasi Mart\u0026iacute;n P\u0026eacute;rez; Belinda Montalb\u0026aacute;n Moreno; Juan Antonio N\u0026uacute;\u0026ntilde;ez Sobrino; Amparo Oltra Ferrando; Mar\u0026iacute;a Gorety Pazos Gonz\u0026aacute;lez; Paola Pimentel C\u0026aacute;ceres; Andrea Marisol S\u0026aacute;nchez; Gloria M\u0026ordf; Serrano Montero; Luc\u0026iacute;a Teijeira S\u0026aacute;nchez; Albert Tuca Rodr\u0026iacute;guez; Miguel \u0026Aacute;ngel Vilar Rodr\u0026iacute;guez\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. 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Documento de consenso sobre prevenci\u0026oacute;n de fragilidad y ca\u0026iacute;das en la persona mayor. Estrategia de Promoci\u0026oacute;n de la Salud y Prevenci\u0026oacute;n en el SNS, 2014. https://www.mscbs.gob.es/profesionales/saludPublica/prevPromocion/Estrategia/docs/FragilidadyCaidas_personamayor.pdf. [accessed 12 February 2021].\u003c/li\u003e\n\u003cli\u003eThe Plos Medicine Editors. Observational studies: Getting clear about transparency. PloS Med 2014;11(8):e1001711. https://doi.org/10.1371/journal.pmed.1001711.\u003c/li\u003e\n\u003cli\u003eMercadante S, Marchetti P, Cuoma A, Caraceni A, Mediati RD, Velluci R et al. Factors influencing the clinical presentation of breakthrough pain in cancer patients. Cancers (Basel) 2018;10:175; https://doi.org/10.3390/cancers10060175.\u003c/li\u003e\n\u003cli\u003eDavies A, Buchanan A, Zeppetella G, Porta-Sales J, Likar R, Weismayr W, et al. Breakthrough cancer pain:An observational study of 1000 European oncology patients. J of Pain Symptom Manage 2013;46 (5):619-28. http://dx.doi.org/10.1016/j.jpainsymman.2012.12.009.\u003c/li\u003e\n\u003cli\u003eBaier P, Ihorst G, Wolff-Vorbeck G, Hull M, Hopt U, Deschler B. Independence and health related quality of life in 200 onco-geriatric surgical patients within 6 months of follow-up: Who is at risk to lose?. Eur J Surg Oncol 2016; 42(12):1890\u0026ndash;7. https://doi.org/10.1016/j.ejso.2016.07.013.\u003c/li\u003e\n\u003cli\u003eFaller H, Br\u0026auml;hler E, H\u0026auml;rter M, Keller M, Schulz H, Wegscheider K, et al. Performance status and depressive symptoms as predictors of quality of life in cancer patients. A structural equation modelling analysis. Psychooncology 2015; 24(11):1456\u0026ndash;62. https://doi.org/10.1002/pon.3811.\u003c/li\u003e\n\u003cli\u003eMinisterio de Sanidad, Servicios Sociales e Igualdad. Encuesta Nacional de Salud. Espa\u0026ntilde;a 2011/12. Calidad de vida relacionada con la salud en adultos: EQ-5D-5L. Serie Informes monogr\u0026aacute;ficos n\u0026ordm; 3. Madrid: Ministerio de Sanidad, Servicios Sociales e Igualdad, 2014. http://www.mscbs.gob.es/estadEstudios/estadisticas/encuestaNacional/encuestaNac2011/informesMonograficos/CVRS_adultos_EQ_5D_5L.pdf. [accessed 12 February 2021].\u003c/li\u003e\n\u003cli\u003ePickard AS, Wilke C, Lin Hsiang-Wen, Lloyd A. Impact of cancer on Health Related Quality of Life: Evidence using the EQ-5D. Barcelona 2006 EuroQol Proceedings, 26-08-2006. https://euroqol.org/search-for-eq-5d-publications/ [accessed 12 February 2021].\u003c/li\u003e\n\u003cli\u003eFortner BV, Okon TA, Portenoy RK. A survey of pain-related hospitalizations, emergency department visits, and physician office visits reported by cancer patients with and without history of breakthrough pain. J Pain 2002; 3: 38-44. https://doi.org/10.1054/jpai.2002.27136.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Sociodemographic and clinical data of frail patients with cancer and breakthrough pain.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"100%\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" width=\"69%\"\u003e\n\u003cp\u003e\u003cstrong\u003eSociodemographic or clinical variable (n=222)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e\u003cstrong\u003e% (n) or mean (95% CI) \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e68.2 (66.6-69.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"0%\"\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e135 (60.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"0%\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e39.2 (87)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eRace\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"0%\"\u003e\n\u003cp\u003eCaucasian\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e80.2 (178)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"0%\"\u003e\n\u003cp\u003eHispanic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e19.4 (43)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"0%\"\u003e\n\u003cp\u003eBlack\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e0.4 (1)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"33%\"\u003e\n\u003cp\u003e\u003cstrong\u003eEmployment status\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"36%\"\u003e\n\u003cp\u003eEmployee\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e2.3 (5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"33%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"36%\"\u003e\n\u003cp\u003eTemporary work disability\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e12.6 (28)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"33%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"36%\"\u003e\n\u003cp\u003ePermanent work disability\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e15.8 (35)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"33%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"36%\"\u003e\n\u003cp\u003eRetirees\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e69.3 (154)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eGij\u0026oacute;n Scale\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"0%\"\u003e\n\u003cp\u003eOverall score (0-20)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e4.9 (4.5-5.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"0%\"\u003e\n\u003cp\u003eNo social-familial risk (\u0026lt;16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e99.6 (221)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"0%\"\u003e\n\u003cp\u003eWith social-familial risk (\u0026ge;16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e0.4 (1)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eBody Mass Index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e25.1 (24.2-25.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" rowspan=\"4\" width=\"33%\"\u003e\n\u003cp\u003e\u003cstrong\u003eClassification according to body mass index (BMI) (n=229)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"35%\"\u003e\n\u003cp\u003eCachexic (BMI \u0026lt;20 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e14.9 (33)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"35%\"\u003e\n\u003cp\u003eNormal (BMI \u0026gt;=20 and \u003cbr /\u003e \u0026lt;25 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e37.4 (83)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"35%\"\u003e\n\u003cp\u003eOverweight (BMI \u0026gt;=25 and \u003cbr /\u003e \u0026lt;30 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e31.1 (69)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"35%\"\u003e\n\u003cp\u003eObese (BMI \u0026gt;=30 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e16.6 (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eKarnofsky performance status\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e63.2 (61-65.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" width=\"69%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Time since cancer diagnosis (months)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e33.9 (27.3-40.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"33%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Primary cancer location\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"36%\"\u003e\n\u003cp\u003eLung\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e33 (73)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"33%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"36%\"\u003e\n\u003cp\u003eGastrointestinal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e23.5 (52)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"33%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"36%\"\u003e\n\u003cp\u003eBreast\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e7.2 (16)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"33%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"36%\"\u003e\n\u003cp\u003eProstate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e5 (11)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"33%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"36%\"\u003e\n\u003cp\u003eOther\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"30%\"\u003e\n\u003cp\u003e31.5 (70)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Characteristics of breakthrough pain in frail patients with cancer.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"100%\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"66%\"\u003e\n\u003cp\u003e\u003cstrong\u003eCharacteristics of breakthrough pain (n= 222)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33%\"\u003e\n\u003cp\u003e\u003cstrong\u003e% (n) or mean (95% CI) \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of daily episodes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e3.8 (3.3-4.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eDuration of episodes (minutes)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e34.6 (28.8-40.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eLocation\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eLumbar\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e30.2 (67)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eAbdomen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e22.5 (50)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eChest\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e21.2 (47)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eHead\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e11.7 (26)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"35%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"31%\"\u003e\n\u003cp\u003eOther\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"33%\"\u003e\n\u003cp\u003e14.4 (32)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eOnset\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eGradual\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e56.8 (126)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eSudden\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e43.2 (96)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eIntensity\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eMild\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e3.2 (7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eModerate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e34.2 (76)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eSevere\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e45.5 (101)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eUnbearable\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e17.1 (38)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eIncidental\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e52.5 (116)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e47.5 (105)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003ePredictable\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e64.9 (144)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e35.1 (78)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eTime of day when it appears\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eAt night\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e12.6 (28)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eDuring the day\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e36.9 (82)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eUnrelated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e50.5 (112)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e\u003cstrong\u003eType of pain\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eSomatic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e27.5 (61)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eVisceral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e24.8 (55)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eNeuropathic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e16.7 (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0%\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003eMixed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\"\u003e\n\u003cp\u003e31.1 (69)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Drugs administered to frail patients with cancer and breakthrough pain for the treatment of chronic pain.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"100%\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"37%\"\u003e\n\u003cp\u003e\u003cstrong\u003eActive ingredient for chronic pain\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"17%\"\u003e\n\u003cp\u003e\u003cstrong\u003eAdministration route\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"17%\"\u003e\n\u003cp\u003e\u003cstrong\u003eDaily frequency\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"27%\"\u003e\n\u003cp\u003e\u003cstrong\u003eDaily dose\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eN\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e\u003cstrong\u003eMean\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eAceclofenac\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e200 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eAmitriptyline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e10 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eBaclofen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e10 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eButylscopolamine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eParenteral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 6 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e40 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eBuprenorphine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eTopical/Transdermal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 72 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e36.8 \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eClonazepam\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e1.5 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"37%\"\u003e\n\u003cp\u003eDexketoprofen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e50 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e75 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eParenteral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e75 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"5\" width=\"37%\"\u003e\n\u003cp\u003eDexamethasone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e3.4 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e8 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e12 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"17%\"\u003e\n\u003cp\u003eParenteral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e12 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e12 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eDuloxetine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e45 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eEslicarbazepine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e800 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eEtoricoxib\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e90 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"6\" width=\"37%\"\u003e\n\u003cp\u003eFentanyl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"17%\"\u003e\n\u003cp\u003eRespiratory/inhaled\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e300 \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 3 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e500 \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"4\" width=\"17%\"\u003e\n\u003cp\u003eTopical/Transdermal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e65.5 \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOn demand\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e56.3 \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 48 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e50 \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 72 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e14.6 \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"37%\"\u003e\n\u003cp\u003eGabapentin\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e600 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e1200 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eIbuprofen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e1800 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eLacosamide\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e200 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eMethadone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e15 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"37%\"\u003e\n\u003cp\u003eMetamizole\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e0.8 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e1826 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eParenteral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e6 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"5\" width=\"37%\"\u003e\n\u003cp\u003eMorphine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e65 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e85.5 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e486 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"17%\"\u003e\n\u003cp\u003eParenteral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e108.5 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOn demand\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e55 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eNaproxen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e700 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"37%\"\u003e\n\u003cp\u003eOxycodone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e68 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e22.5 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 6 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e20 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"37%\"\u003e\n\u003cp\u003eOxycodone/Naloxone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e6.3 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e42.5 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e90 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"37%\"\u003e\n\u003cp\u003eParacetamol\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e2797 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 3 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e5000 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eParenteral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e2400 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eParacetamol/codeine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e3000 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003ePrednisone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e5 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"37%\"\u003e\n\u003cp\u003ePregabalin\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e43.8 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e160 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e75 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"37%\"\u003e\n\u003cp\u003eTapentadol\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 24 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e150 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e155 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"4\" width=\"37%\"\u003e\n\u003cp\u003eTramadol\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e150 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e156 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 6 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e400 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eParenteral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 12 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e200 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"37%\"\u003e\n\u003cp\u003eTramadol/paracetamol\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"17%\"\u003e\n\u003cp\u003eEvery 8 h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"21%\"\u003e\n\u003cp\u003e225 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ea. N: number of patients with the treatment, patients received one or more treatments.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Drugs administered to frail patients with cancer for the treatment of breakthrough pain.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"100%\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"25%\"\u003e\n\u003cp\u003e\u003cstrong\u003eActive ingredient for breakthrough pain\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"16%\"\u003e\n\u003cp\u003e\u003cstrong\u003eRoute\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"20%\"\u003e\n\u003cp\u003e\u003cstrong\u003eUnit dose\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e\u003cstrong\u003eUnit dose in the Mercadante study[26]\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e\u003cstrong\u003eN\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e\u003cstrong\u003eMean\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e\u003cstrong\u003eMean dose (SD)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"25%\"\u003e\n\u003cp\u003eDexketoprofen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e25 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"25%\"\u003e\n\u003cp\u003eDuloxetine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e30 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"5\" width=\"25%\"\u003e\n\u003cp\u003eFentanyl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e190 \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e(71.1-309)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e234.6 (183.1) \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eSublingual\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e161.7 \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e(139-184)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e231.4 (171.1) \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eNasal with pectin\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e59\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e155.9 \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e(130-182)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e167.7 (125.7) \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eNasal without pectin\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e100 \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e100 (50.7) \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eTransdermal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e29 \u0026mu;g\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e(-19-77)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"25%\"\u003e\n\u003cp\u003eIbuprofen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e400 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"25%\"\u003e\n\u003cp\u003eMetamizole\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e231.2 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e(-159-621)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eParenteral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e2 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e(2-2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"25%\"\u003e\n\u003cp\u003eMetamizole/\u003c/p\u003e\n\u003cp\u003eScopolamine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eParenteral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e2500/20 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"25%\"\u003e\n\u003cp\u003eMorphine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e11.7 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e(8-15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e11.8 (8.2) mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eParenteral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e10.7 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e(7-14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e8.2 (6.1) mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"25%\"\u003e\n\u003cp\u003eOxycodone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e9.2 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e(-2-20)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"25%\"\u003e\n\u003cp\u003eOxycodone/Naloxone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e10 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"25%\"\u003e\n\u003cp\u003eParacetamol\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e683.3 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e(288-1078)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eParenteral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e1000 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e(1000-1000)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"25%\"\u003e\n\u003cp\u003eTramadol\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"16%\"\u003e\n\u003cp\u003eOral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6%\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e54.2 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"18%\"\u003e\n\u003cp\u003e(44-65)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ea. N: number of patients with the treatment.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cancer, breakthrough pain, frailty.","lastPublishedDoi":"10.21203/rs.3.rs-390548/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-390548/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe purpose of this study was to analyse the clinical management and quality of life of frail patients with cancer, chronic pain and breakthrough pain (BTP) and to assess whether treatment was conditioned by their frailty status.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThis was an observational study in adult frail patients with cancer, chronic background pain and BTP. Outcomes of interest collected include clinical and sociodemographic data, Karnofsky Performance Status, quality of life (EuroQoL-5D-5L), chronic pain and BTP characteristics, as well as treatments administered for their control.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eA total of 222 patients were included with a mean age of 68 years (range 24-91), 60.5% men, with a mean Karnofsky of 63.2%. The number of daily episodes of BTP was 3.8 (95% CI 3.3-4.3), with a duration of 34.6 minutes (95% CI 28.8-40.3), and 56.8% had a gradual onset. Opioids were administered to 88.3% of patients for the chronic pain, and to 83.8% for BTP. The treatment's daily doses administered for chronic pain and BTP did not differ from those usually recommended. Quality of life was significantly worst in frail patients with cancer than no frail patients and was related to performance status (p\u0026lt;0.001) and to the social-familial status (p=0.045). \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eBTP in frail patients with cancer presents with more episodes, of a shorter duration and more gradual onset compared to other patients with BTP, and Quality of life was seriously affected. No relevant differences were seen in the doses or method of administration of treatments for chronic pain and BTP in frail patients with cancer as compared to the standard recommendations for non-frail patients. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eNot applicable to the study.\u003c/p\u003e","manuscriptTitle":"Analysis of the Clinical Management and Quality of Life of Frail Patients with Cancer and Breakthrough Pain in Clinical Practice.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-04-05 14:30:41","doi":"10.21203/rs.3.rs-390548/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2021-04-12T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-03-04T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-03-03T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-03-03T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"caaa9a49-bca9-4bf5-b1a9-46ec5bf3f67e","owner":[],"postedDate":"April 5th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":3409585,"name":"Cancer Biology"},{"id":3409586,"name":"Oncology"}],"tags":[],"updatedAt":"2021-04-05T14:30:41+00:00","versionOfRecord":[],"versionCreatedAt":"2021-04-05 14:30:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-390548","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-390548","identity":"rs-390548","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}