Background: Breakthrough cancer pain (BTcP) is defined according to its principal characteristics: high intensity, short time interval between onset and peak intensity, short duration, potential recurrence over 24 h and non-responsiveness to standard analgesic regimes. The Edmonton Classification System for Cancer Pain (ECS-CP) is a classification tool that evaluates different dimensions of pain. The aim of this study was to measure prevalence and the main characteristics of BTcP in a sample of advanced cancer patients and to explore the complexity observed when ECS-CP is incorporated into BTcP diagnostics algorithm. Methods: Descriptive prevalence study (Retrospective chart review). Davies’ algorithm was used to identify BTcP and ECS-CP was used to recognize appropriate dimensions of pain. The study was conducted in a sample of advanced cancer patients attending hospital outpatient clinic in Lleida, Spain. 277 patients were included from 01/01/2014 to 31/12/2015. No direct contact was made with participants. The following information was extracted from the palliative care outpatient clinic database: age, gender, civil status, cognitive impairment status, functional performance status and variables related to tumour. Only BTcP cases were included. Results: Prevalence of BTcP was 39.34% (63.9% men). Mean of age was 68.2 years. Main diagnosis was lung cancer (n = 154; 31.6%). Metastases were diagnosed in 83% of the sample. 138 patients (49.8%) were diagnosed with 1 type of BTcP and 139 (50.2%) were diagnosed with more than one type of BTcP. In total, 488 different types of BTcP were recorded (mean 1.75 ± 0, 9), 244 of these types (50%) presented a component of neuropathic pain. Addictive behaviour, measured through CAGE test, was present in 29.2% (N = 81) of the patients and psychological distress was present in 40.8% (n = 113). Conclusions: Prevalence of BTcP (39.34%) is similar to the one reflected in the existing literature. Study results indicate that the routine use of ECS-CP in a clinical setting allows us to detect more than one type of BTcP as well as additional complexity associated with pain (neuropathic, addictive behavior and psychological distress). Keywords: Breakthrough cancer pain, Palliative care, ECS-CP, Neuropathic pain, Addictive behaviour, Psychological distress * Correspondence: firstname.lastname@example.org Faculty of Nursing and Phisiotherapy, Universitat de Lleida, Montserrat Roig 2, 25198 Lleida, Spain Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Canal-Sotelo et al. BMC Palliative Care (2018) 17:81 Page 2 of 8 Background enhance both the quality of life and the functionalism of In 1989, Portenoy and Hagen  defined breakthrough the patient . cancer pain (BTcP) as the transient exacerbation of pain The first choice of treatment is always oral and in occurring in a patient with otherwise stable pain in re- many cases, for the treatment of BTcP, the choice is ceipt of chronic opioid therapy. This pain is one of the fast bioavailability treatments such as fentanyl. The most difficult pain syndromes to treat. The term en- rapid bioavailability of fentanyl-based ROOs may lead compasses a diverse group of transient pains that vary to episodes of abuse of these drugs; therefore it is ad- in their relationship to the fixed analgesic dose, tem- visabletominimizethe risk with adetailedappropri- poral characteristics, precipitating events, predictability, ately assessment [33, 34]. pathophysiology, and aetiology [1, 2]. The Edmonton Classification System for Cancer Pain Later, BTcP was redefined as a transient exacerbation (ECS-CP) derives from the Revised Edmonton Staging of pain that occurs either spontaneously, or in relation System (rESS) from which construct, inter-rater reliability, to a specific predictable or unpredictable trigger, despite and predictive validity evidence have contributed to the relatively stable and adequately controlled background development of the ECS-CP. The five features of cancer pain . More recently, other authors [4–7] have im- pain included -Pain Mechanism (N), Incident Pain (I), proved BTcP definition by adding severity of intensity Psychological Distress (P), Addictive Behavior (A) and and the length between 30 and 60 min. Cognitive Function (C)- have demonstrated value in pre- Prevalence of BTcP varies between 19 and 95% [8–11]. dicting pain management complexity [35, 36]. This is explained by the different definitions found in The ECS-CP is a clinically relevant systematic frame- the literature and also depending on the area where the work, which is able to detect differences in salient data are collected (inpatient or outpatient patients). pain classification features across diverse settings and The prevalence of BTcP assessed in outpatient clinics countries . is 39.9% and in those assessed in palliative care units, is It is known that BTcP is difficult to diagnose and to 80.5% . treat. We hypothesized that if we add the ECS-CP dur- It is therefore difficult to diagnose BTcP. For this rea- ing the diagnosis process, we find an added complexity son, many Scientific Societies related to cancer, palliative together with the incident features of the cancer pain. care and pain, work to clarify the definition and the This is because we can find other characteristics of pain accurate diagnosis of BTcP [13–17]. such as the neuropathic component, addiction and psy- In the same way, different instruments have been de- chological discomfort. fined to facilitate the diagnostic approach of BTcP. We Therefore, the objectives of this retrospective review highlight the Alberta Breakthrough Pain Assessment were: Tool for Cancer Patients , the breakthrough pain as- sessment tool (BAT) in cancer patients  and the Italian 1. To describe the characteristics of the population Questionnaire for Breakthrough Pain (IQ-BTP) . studied and the prevalence of BTcP in a sample of To improve the sensitivity of the diagnosis of BTcP, advanced cancer patients treated at an outpatient several authors developed the so-called “Davies algo- clinic. rithm” , recently validated by Weber K et al. . 2. To determine the number of different types of Although the use of this algorithm is widespread, it is BTcP diagnosed in each patient, regardless the not designed to replace clinical assessment. number of episodes of BTcP. Literature refers to BTcP as a single clinical entity with 3. To explore the different pain features associated to several possible episodes in a single patient and the fact the diagnosis of BTcP that more than one different types of BTcP with several episodes each in the same patient has not yet been Methods explored [16, 23, 24]. This was a retrospective and anonymous database re- The pharmacological treatment of BTcP is based on view of the patients attending for the first time at the use of the three-step ladder of the WHO [25, 26]. Palliative Care outpatient clinic, which is maintained Considering the characteristics of BTcP in terms of at the Lleida University Hospital in Catalonia (Spain). temporality and intensity, only Rapid Onset Opioids This study was approved by the Ethics Committee of (ROOs), mainly fentanyl, have been shown to be effect- the Hospital Universitari Arnau de Vilanova in Lleida. ive [27–29]. Zeppetella and Davies  conclude that All data-analysis was performed anonymously without both oral and intranasal-Trans-mucosal fentanyl are ef- an additional informed consent, according to its recom- fective for the treatment of BTcP episodes. mendations. The administrative permissions required Early pharmacological approach is the cornerstone of were obtained in order to review patient records and use the treatment of BTcP . Its improvement will also the data. Canal-Sotelo et al. BMC Palliative Care (2018) 17:81 Page 3 of 8 This Palliative Care outpatient clinic attends advanced This is the usual protocol applied in order to study pain cancer patients early in the disease course as well as pa- when a patient is assessed first time at the outpatient clinic. tients that are not receiving active treatment. The patients were referred to the clinic by their reference oncologist Data collection and the palliative care consultation team was the respon- The following information was extracted from the chart re- sible organ of the pain management. view: age, gender, civil status, cognitive status measured Inclusion criteria: age > 18 years, diagnosis of advanced with Pfeiffer test [39, 40], functional performance status cancer (non haematological) assisted at the outpatient measured with Barthel test [41, 42] and with Palliative clinic of the Palliative care outpatient clinic suffering, Performance Scale version 2 test (PPSv2) [43, 44]. Variables from BTcP due to cancer and without any cognitive im- related to the tumour were obtained (primary tumour pairment (Pfeiffer test ≥ 4 errors). End-of-dose pain was diagnosis, metastatic disease and locally advanced disease). specifically excluded. We also extracted the information related to BTcP as We defined BTcP according to Boceta et al. as a following: transitory exacerbation of pain lasting less than 60 min, which occurs spontaneously or in association with a spe- – Related Factors: predictable, unpredictable or cific predictable or unpredictable trigger at some point idiopathic (volitional, non-volitional or idiopathic). during the day in cancer patients, despite relatively and – Cause of pain: tumour, treatments received or adequately controlled background pain. BTcP was con- idiopathic cause. sidered as those that have different characteristics in – Intensity of pain: measured through a VAS scale. terms of localization, intensity, mechanisms that trigger Minimum and maximum intensity were recorded. it or intrinsic characteristics of pain (neuropathic vs. The difference between VAS minimum intensity nociceptive). The same type of BTcP can present with (VAS min) and VAS maximum intensity (VAS max) several episodes (maximum 4 episodes per day). The lit- should be ≥ 3 points measured with scale from erature review shows that there is not a broad consensus 0 to 10. about definition of BTcP therefore, to facilitate the methodology of data collection; we included equal terms The ECS-CP was applied in order to detect additional BTcP and incidental pain. pain features other than incident pain in the same pa- A physician, also responsible for assessing pain and tient. The neuropathic component of pain was assessed other symptoms, evaluated all the patients attended in through the Doleur Neuropathique-4 questionnaire the outpatient clinic. Pain was assessed using a Visual (DN4) [45, 46] altogether with the clinical examination. Analogic Scale (VAS) and the cut-off value (VAS scale) For the psychological distress we followed the Clinical of patients for their background pain was VAS ≤ 3 during Practice Guidelines in Oncology (NCCN) and a VAS ≥ 4 the previous 7 days. All patients who reported ad- in either anxiety or depression was the cut-off point equately controlled background pain (VAS ≤ 3) in the . Regarding the addictive behaviour only the addic- previous week were further evaluated exhaustively. The tion to alcohol was collected and measured through Cut procedure to diagnose BTcP was done following the al- down, Annoyed, Guilty and Eye-opener questionnaire gorithm of Davies  and according to the consensus (CAGE) . Two or more “yes” responses indicated the recommendations from the Spanish Pain Society. The al- possibility of alcoholism. gorithm indicates that baseline pain must be adequately For each pain features detected by the ECS-CP controlled before a diagnosis of BTcP can be considered. (NIPAC), one point was given. Each BTcP were located anatomically in the painful area Even if the number of BTcP episodes were specifically and each patient could present different types of pain. For registered in the patients files, they were not included in each type of BTcP, the ECS-CP test was later applied to as- the data analysis. sess additional complexity. The ECS-CP classifies the dif- ferent pain features according to its origin. This way, the Data analysis neuropathic and incident component of pain can be sec- The data included all patients attending the outpatient ondary to the tumor itself while the psychological discom- clinic of the Catalan University Hospital Arnau de Vilanova fort and addictive behaviour can be considered personality of Lleida between 2014 and 2015. The information for the traits. Therefore, the analysis of both the neuropathic (N) study was extracted between June and October 2016. and the incident (I) component of pain was done over the The study was carried out in two separate phases; in the total number of different types of BTcP detected and the first phase the data analyzed was related to the total num- Psychological (P) and addictive (A) traits were analysed ber of patients with pain included consecutively in the over the total number of patients included. The Cognitive study and this sample was further studied according to the (C) component was specifically excluded. number of different types of pain found (1 types vs. > 1 type Canal-Sotelo et al. BMC Palliative Care (2018) 17:81 Page 4 of 8 of pain). In the second phase, data analyzed was related to continuous and categorical variables, respectively. Statis- the total number of different types of BTcP individualized tical significance was assumed at a 0.05 level (P <0.05). after having used the ECS-CP in the diagnostic algorithm and the sample was also further analyzed depending of the Results pain intensity. We considered mild and moderate pain if The palliative care team visited a total of 1276 patients the VAS < 7 and severe pain included VAS ≥ 7. for the first time at the University Hospital Arnau de Statistical analyses were conducted using SPSS Statistics Vilanova in Lleida, Catalonia (Spain) between January 20 (IBM Corporation) and Microsoft Excel (Microsoft 2014 and December 2015. 704 of them (55.17%) Corporation) software . Continuous variables were attended the outpatient clinic. 303 patients had pain, summarized as means and standard deviations (SD). and 277 were diagnosed of BTcP and included to the Categorical variables were summarized as percentages chart review study. Mean age was 68.2 ± 13 years while (absolute numbers). Univariate analysis was performed men accounted for 67.9% of the sample. Lung cancer using the Wilcoxon or Chi square test without correc- (31%) was the most prevalent cancer diagnosis and tion for continuity for comparison among groups of metastatic disease was found in 83% of the sample. Fig. 1 Flow Chart of BTcP diagnosis process. Flow chart of patients visited first time in the Palliative care outpatient clinic. Prevalence of BTcP. Patients diagnosed with BTcP and different types of BTcP according to the ECS-CP classification Canal-Sotelo et al. BMC Palliative Care (2018) 17:81 Page 5 of 8 A prevalence of 39.34% of BTcP (277/704 patients) was Table 1 Sociodemographic and medical characteristics of the patients (N = 277) in relation to the number of BTcP found. A total of 488 different types of BTcP were de- tected (mean of 1.75 ± 0.9 types of BTcP per patient). Up Total BTcP p (n = 277) to 5 different types of BTcP were found among the pa- BTcP (1 type) BTcP (> 1 type) N = 138 N = 139 tients and 50,2% of patients (N = 139) accounted for ≥ 2 Age (years) 68.2 ± 13 70.4 ± 13 66 ± 12 0.002 types of BTcP (Fig. 1). Main characteristics of the population studied are Gender (men) (%) 67.9 73.2 62.6 0.059 showed in Table 1. Addictive behavior was detected in Civil Status (%) 0.854 29.2% of the sample and the psychological discomfort Married/couple 71.1 69.6 72.7 was detected in 40.8%. This table also shows the results Single 6.5 5.8 7.2 according to two groups of patients (1 type vs > 1 type). Separated/divorced 7.6 8 7.2 The group of patients with > 1 type was younger (66 ± 12, Widowed 10.8 11.6 10.1 p = 0.002), had more metastatic disease (90.6%, p = 0.001) and presented with more psychological discomfort (47.5%, Missing 4 5.1 2.9 p= 0.023). Patients with 1 type of BTcP presented ad- Type tumor (%) 0.508 dictive behavior (CAGE) (34.8%, p = 0.043). Lung 31 31.2 30.9 In Table 2, the analysis was performed taking into ac- Upper digestive 19.9 21 18.7 count the number of different types of BTcP detected Lower digestive 19.1 18.8 19.4 (N = 488). The use of the ECS-CP tool on each type of Ear-Nose and 8.7 10 7.2 BTcP allowed us to detect that, together with the inci- Throat dent feature of pain, 50% (N = 244) had a neuropathic Genitourinary 8.7 6.5 10.8 component. Non-volitional component of BTcP was male detected in the 63.7% of the sample. The sum of the dif- Genitourinary 4 2.2 5.8 ferent pain features detected by the ECS-CP (NIPAC) female when applied on the sample of 488 different types of Other 8.7 10.1 7.2 BTcP is 2.2 ± 1. Metastatic disease (%) 83 75.4 90.6 0.001 Discussion Pfeiffer Test 0.8 ± 1 0.9 ± 1 0.6 ± 1 0.068 This retrospective study was designed to determine several Barthel Test 87 ± 17 87 ± 18 87 ± 15 0.409 outcomes related to BTcP in a sample of advanced cancer PPSv2 Test 64 ± 12 64 ± 12 63 ± 11 0.131 patients who attended the outpatient clinic of a University Pain features hospital during a two-year period (2014–2015). Addictive 29.2 34.8 23.7 0.043 We identified a prevalence of 39.34% of BTcP in the Psychological 40.8 34.1 47.5 0.023 sample of patients screened for the study. The applica- tion of Davies algorithm and a close clinical examination Number of BTcP 1.75 ± 0.9 types were the cornerstone for defining pain. This result is mean ± standard deviation consistent with Deandrea et al.  who after a biblio- b 2 Comparison between groups with the χ test and for continuous variables graphic research, stated a prevalence of BTcP of 39.9% with the Mann-Whitney test for cancer patients attended at the outpatient clinic. Similar outcome data are reported by Margarit et al.  127 patients (45.9%) presented with 2 or 3 different who, after reviewing data from the American Pain types of BTcP. Foundation, show a prevalence of 35% for those can- Younger patients and those presenting with metastatic cer patients seen on an ambulatory regime. disease variables were found statistically significant. To our knowledge, this study provides the first data The classification ECS-CP provides further insight into regarding the fact that a single patient can present with several characteristics of pain like neuropathic, psycho- more than one type of BTcP. Previous studies only ad- logical distress and addictive behavior features. As the dress this subject as a single patient having different ep- Incident component of pain is already included in the isodes of thesameBTcP. On the current study, we ECS-CP, all types of pain found in our study had a found that a total of 488 different types of BTcP were BTcP component. The addictive behaviour (A) was assessed in a sample of 277 patients. Each patient had sensibly higher (29.2%) than the found in the literature. an average of 1.75 BTcP. We remark that more than Parsons et al. and Devetal.  found in their half of the patients (139/277) were found to report studies a prevalence of addictive behaviour of 17% in more than one type of BTcP. Up to 12 patients pre- cancer patients attending an outpatient clinic while sented with 4 or 5 different types of BTcP (4.3%) while Chow et al.  found a poor 7% prevalence rate in an Canal-Sotelo et al. BMC Palliative Care (2018) 17:81 Page 6 of 8 Table 2 Characteristics of episodes of incidental pain (n = 488) – This is a retrospective study and prevalence rates are according to intensity (maximum VAS ≥ 7) reported from a single institution and a single SAMPLE VAS MAX < 7 VAS MAX ≥ 7 p physician recorded the data available from medical (n = 488) (n = 305) (n = 183) records during clinical interviews. Due to Tumour 93,0 91,8 95,1 0,168 – This study includes BTcP and incidental pain in Due to treatment 8,0 8,5 7,1 0,575 equal terms. – Data from addiction behaviour only included alcohol Volitional 36,3 36,7 35,5 0,789 screening through the CAGE questionnaire. Non volitional 63,7 64,1 35,9 0,618 – This study included a large cohort of patients who Neuropathic condition 50,0 45,4 63,0 0,001 had BTcP. ∑NIPAC 2,2 ± 1 2,2 ± 1 2,3 ± 1 0,044 – This study supports the hypothesis that a single Type tumor 0,007 patient can present more than one type of BTcP. Lung 31,6 35,4 25,1 – This study supports the use of screening tools to better categorize diagnose of Cancer pain. Upper digestive 18,0 18,7 16,9 Lower digestive 20,1 20,3 19,7 Conclusions ENT 7,6 6,9 8,7 Our study provides data regarding prevalence of BTcP in Genitourinary male 8,4 8,9 7,7 a palliative care outpatient clinic in a single Teaching Genitourinary female 5,1 4,3 6,7 Hospital and the result of 39.94% is similar to those Other 9,2 5,6 15,3 found in the literature. This retrospective chart review allows determining the Values as percentage mean ± standard deviation number of different types of BTcP diagnosed in each pa- b 2 Comparison between groups with the de χ test and for continuous variables tient, regardless the number of episodes of BTcP. This is with the Mann-Whitney test possible with the routine use of the ECS-CP in tandem outpatient palliative radiotherapy clinic. Even if all studies with the Algorithm of Davies when exploring BTcP in screened the addictive behaviour using the CAGE ques- cancer patients. tionnaire, differences found can be explained by the fact This study explores the different pain features associated that we recorded the CAGE in current or former drinkers. to the diagnosis of BTcP. Clinicians have to take into ac- The sample of 488 different types of pain found was count several pain features such as the neuropathic nature further divided according to pain intensity. Only neuro- of pain, psychological distress and addictive behaviour, as pathic nature of pain, the summation of the ECS-CP and the optimal therapeutic approach can change. the type of cancer showed significant statistical differences. The existence of more than one type of BTcP in each The ECS-CP has demonstrated its utility in routine patient adds more complexity to the pain assessment. clinical practice. Arthur et al.  found that neuro- Abbreviations pathic pain and psychological distress were associated A: Addictive Behavior; BAT: Breakthrough pain assessment tool; with higher pain intensity. Also a higher sum of ECS-CP BTcP: Breakthrough Cancer Pain; C: Cognitive Function; CAGE: Cut down, annoyed, guilty and eye-opener questionnaire; DN4: Doleur neuropathique-4 features was associated with higher pain intensity. More questionnaire; ECS-CP: Edmonton Classification System for Cancer Pain; recently the same author found that increasing sum of ENT: Ear, Nose and Throat; I: Incident Pain; IQ-BTP: Italian Questionnaire for ECS-CP features was not predictive of pain management Breakthrough Pain; N: Pain Mechanism; NCCN: Clinical Practice Guidelines in Oncology; P: Psychological Distress; PPSv2: Palliative Performance Scale complexity. Our study shows that a higher sum of version 2 test; rESS: Revised Edmonton Staging System; ROOs: Rapid Onset ECS-CP features was found among the group of types of Opioids; SD: standard deviations; VAS max: VAS maximum intensity; BTcP with a VAS intensity ≥ 7. VAS min: VAS minimum intensity; VAS: Visual analogic Scale However the study has limitations; first, the study was Authors’ contributors carried out in a single institution and data available from JCS participated in the design of the work, carried out the study and medical records were recorded by a single physician dur- had the main responsibility for writing the manuscript and for the final approval, EBG participated in conceiving the study, writing the manuscript ing clinical interviews. Second, data from addiction be- and participated in the final approval of the version to be published, haviour only included alcohol screening through the PJL revised it critically and approved of the version to be published, JTC CAGE questionnaire. supported data analysis and writing the manuscript. NAT, RGR and MRG participated in the interpretation of data for the work and JCS, PJL, EBG Our study did not aim to analyse any specific pharma- and JTC have made significant contributions to this topic in the field of cological treatment the patients received. Our study palliative care. All authors read and approved the final manuscript and shows a high prevalence of the neuropathic component have assumed accountability for all aspects of the work. of BTcP, further studies have to address this finding. Funding The strengths and limitations of this study are the This research received no specific grant from any funding agency in the following: public, commercial or not-for-profit sectors. 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BMC Palliative Care – Springer Journals
Published: May 28, 2018
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