Current management of breakthrough

cancer pain according to physicians from

pain units in Spain

Grupo de trabajo de dolor oncológico of

the SED (Sociedad Española de Dolor)

Clinical and Translational Oncology

ISSN 1699-048X

Clin Transl Oncol

DOI 10.1007/s12094-019-02044-8

1 23
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Clinical and Translational Oncology
https://doi.org/10.1007/s12094-019-02044-8

RESEARCH ARTICLE

Current management of breakthrough cancer pain according

to physicians from pain units in Spain
F. V. Estévez1   · Mª D. L. Alarcón2 · V. Mayoral3 · M. de Madariaga4 · C. Margarit5 · J. A. Duran6 ·
J. M. T. Martín‑Arroyo7 · A. Carregal8 · Grupo de trabajo de dolor oncológico of the SED (Sociedad Española de
Dolor)

Received: 26 September 2018 / Accepted: 14 January 2019

© Federación de Sociedades Españolas de Oncología (FESEO) 2019

Abstract
Purpose  Current evidence suggests the need to improve the management of breakthrough cancer pain (BTcP). For this
reason, we aimed to assess the opinion of a panel of experts composed exclusively of physicians from pain units, who play
a major role in BTcP diagnosis and treatment, regarding the key aspects of BTcP management.
Methods  An ad hoc questionnaire was developed to collect real-world data on the management of BTcP. The questionnaire
had 5 parts: (a) organizational aspects of pain units (n = 12), (b) definition and diagnosis (n = 3), (c) screening (n = 3), (d)
treatment (n = 8), and (e) follow-up (n = 7).
Results  A total of 89 pain-unit physicians from 13 different Spanish regions were polled. Most of them agreed on the tra-
ditional definition of BTcP (78.9%) and the key features of BTcP (92.1%). However, only 30.3% of participants used the
Davies’ algorithm for BTcP diagnosis. Respondents preferred to prescribe rapid-onset opioids [mean 77.0% (SD 26.7%)],
and most recommended transmucosal fentanyl formulations as the first option for BTcP. There was also considerable agree-
ment (77.5%) on the need for early follow-up (48–72 h) after treatment initiation. Finally, 65.2% of participants believed
that more than 10% of their patients underused rapid-onset opioids.
Conclusions  There was broad agreement among pain experts on many important areas of BTcP management, except for the
diagnostic method. Pain-unit physicians suggest that rapid-onset opioids may be underused by BTcP patients in Spain, an
important issue that need to be evaluated in future studies.

Keywords  Breakthrough cancer pain · Pain units · Consensus · Opioids

Introduction

Breakthrough cancer pain (BTcP) was first defined by Por-

tenoy in 1990 [1], although the most widely accepted defini-
Electronic supplementary material  The online version of this tion is the one proposed by Davies et al. [2, 3]: “a transient
article (https​://doi.org/10.1007/s1209​4-019-02044​-8) contains exacerbation of pain that occurs either spontaneously or in
supplementary material, which is available to authorized users.

5
* F. V. Estévez Pain Unit, Hospital General Universitario de Alicante,
franvilles@hotmail.com Alicante, Spain
6
1 Pain Unit, Hospital Universitario Nuestra Señora de
Pain Unit, Consorcio Hospital Provincial de Castellón,
Candelaria, Hospital en Santa Cruz de Tenerife, Tenerife,
Castellón, Spain
Spain
2
Pain Unit, Hospital General Universitario de Valencia, 7
Pain Unit, Hospital Puerta del Mar, Cádiz, Spain
Valencia, Spain
8
3 Pain Unit, Complexo Hospitalario Universitario de Vigo
Pain Unit, Hospital Universitari de Bellvitge, Barcelona,
(CHUVI), Pontevedra, Spain
Spain
4
Pain Unit, Hospital Universitario Infanta Sofía, Madrid,
Spain

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Clinical and Translational Oncology

relation to a specific predictable or unpredictable trigger, agreement and discrepancy among them to assess improve-
despite relatively stable and adequately controlled back- ments in BTcP management in future studies.
ground pain”.
BTcP is mainly a result of the neoplasm itself (70–80%
of cases) or a result of anticancer treatment in 10–20% of Methods
cases [4], and is most common in head and neck cancer
(70%), followed by gastrointestinal (59%), lung (55%) and Study design
breast cancer (52%) [5]. Overall, the prevalence of BTcP
is very high—a recent systematic review estimated that it An observational, cross-sectional study based on a real-
affects approximately 60% of cancer patients [6]. In addi- world survey.
tion, BTcP greatly affects patient quality of life, patient’s
emotional and physical health and their capacity to perform
routine tasks [7, 8]. Ethical considerations
In the actuality, the Alberta Breakthrough Pain Assess-
ment Tool (ABPAT), specifically designed for BTcP in the All participants were contacted via e-mail, informed about
clinical trials setting, has been validated to facilitate the cor- the study, and gave their consent to participate prior to inclu-
rect diagnostic of BTcP in cancer patients [9]. Additionally, sion. Since this study consisted of a survey of expert opin-
in 2009, Davies et al. [2, 3] published a diagnostic algo- ions and no patient data were collected, approval from the
rithm. However, cancer pain specialists have yet to agree institutional review board was not required.
on the fundamental aspects of BTcP diagnosis: whether
the presence of controlled background pain is a prerequi-
Scientific committee
site for BTcP diagnosis, or whether end-dose pain flares or
pain flares during titration should be considered BTcP epi-
The scientific committee was formed of the authors of this
sodes. Moreover, the most controversial issue continues to
manuscript, all of whom have extensive experience in the
be whether the theoretical definition should include opioids
management of BTcP. The members of the scientific com-
or other analgesics as the treatment of choice for background
mittee were responsible for developing the study methodol-
pain.
ogy, preparing and distributing the survey and study pro-
Management is equally complex and requires the use of
tocol, performing the statistical analysis, and interpreting
appropriate breakthrough medication [10]. Rapid-onset opi-
the results.
oids (ROOs) adapt well and have been shown to be more
effective than placebo or oral morphine in the treatment of
BTcP [11]. Based on this evidence, national [12] and inter- Participants
national guidelines [13] recommend ROOs for the treat-
ment of BTcP. However, despite these recommendations All study participants were pain management specialists,
and the growing evidence supporting the use of ROOs in and all were required to have experience in diagnosing and
recent years, several publications [6, 14] suggest that a high treating cancer pain. The sample of pain-unit physicians
proportion of cancer patients receive suboptimal analgesia, was selected from a diverse geographic area in Spain that
revealing the need to improve diagnosis and treatment of included 13 of the country’s autonomous communities.
BTcP patients.
Pain units consist of an interdisciplinary team of medi- Questionnaire
cal specialists aimed to improve patient pain management.
Recent evidence shows that pain specialists refine and An ad hoc electronic microsite 33-item questionnaire was
improve the diagnosis and treatment of patients referred to developed to collect real-world data on the management of
their units and improve their outcomes [15]. This clearly BTcP (Supplementary Table 1); in particular, the physicians’
demonstrates the importance of pain units in pain manage- personal opinion of the key aspects. The questionnaire was
ment; however, to the best of our knowledge, the opinion of divided into five sections: (a) organizational aspects of pain
pain-unit physicians on current BTcP management has never units (n = 12), (b) definition and diagnosis (n = 3), (c) screen-
been evaluated in the literature. ing (n = 3), (d) treatment (n = 8) and (e) follow-up (n = 7)
This situation prompted us to explore the opinion of a (Supplementary Table 2).
panel of experts composed solely of pain specialists from
Spanish pain units regarding the key aspects of the man-
agement of BTcP. We also sought to identify points of

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Statistical analysis
Data were analyzed descriptively using R statistics pack-
age version 3.2.5. Categorical variables were described as
absolute and relative frequencies, whereas central tendency
and dispersion were reported for quantitative variables. The
Chi-square test was used to compare the scores obtained
from each question. For all tests, statistical significance was
set at p < 0.05.
Results
A total of 89 eligible pain-unit specialists with experience
in cancer pain treatment were selected for the study. The
physicians are attached to 89 different units located in 13
different Spanish autonomous communities.
Organizational aspects of pain units
Answers to questions about the organizational aspects of
pain units are summarized in Table 1.
Most respondents (89.8%) were attached to level-II and
-III pain units with uni- and interdisciplinary specialized
pain management. Most pain units consist of a team of
diverse medical specialists and other healthcare profession-
als, mostly anesthesiologists. Pain units had a mean of 1.6
(SD 1.6) full-time and 3.4 (SD 2.1) part-time physicians.
Nearly half of the respondents (47.2%) are attached to units
with a catchment area of > 300,000 inhabitant. More than
half (56.2%) estimated that between 1000 and 5000 patients
with chronic pain were seen in their pain units in the preced-
ing year, of which < 10% presented oncologic pain (68.5%).
According to the pain-unit experts, most of their hos-
pitals have medical oncology (94.4%) and palliative care
(80.9%) units; however, 62.9% stated that their hospitals had
not implemented a pain-unit referral protocol. Finally, most
physicians polled reported that their pain units use inter-
ventional techniques for oncologic pain treatment, such as
nerve block (82.0%) or intrathecal pump placement (67.4%).
BTcP definition and diagnosis
Almost 80% of physicians polled agreed (43.8% strongly
agreed) with the traditional definition of BTcP proposed by
Portenoy et al. [1]. Similarly, agreement was strong (92.1%)
on the proposed features: rapid onset pain (between 3 and
5 min), moderate–severe intensity (VAS 4–10), duration
between 1 min and 4 h (average of 30 min) and major impact
on patient quality of life. However, only 30.3% of respond-
ents used the Davies’ Adapted Diagnostic Algorithm as their
gold standard for diagnosis, 49.5% used it only occasionally,
and 20.2% never used it.
BTcP screening
Most physicians in our study agreed that BTcP has two
mechanisms of onset: idiopathic or spontaneous and inciden-
tal (84.3%). Additionally, most participants agreed that the
most important risk factor is advanced cancer disease, fol-
lowed by aggressive anticancer treatments (Table 2). Inter-
estingly, only 36% of physicians initiate a BTcP treatment
exclusively when it is caused by the advanced or metastatic
tumor; the remaining 64.0% prescribe it in cancer patients
also when the pain is not directly related with cancer disease.
BTcP treatment
The consensus among physicians polled was that most
patients suffering from BTcP should be treated with opi-
oid-based therapy [mean 77.0% (SD 26.7%)], followed by
adjuvants [mean 49.9% (SD 29.7%)], while only a mean of
32.9% (SD 27.1%) consider that BTcP patients should be
managed with interventional techniques (Table 3). Among
the pharmacotherapies, physicians preferred ROOs for most
patients [mean 77.0% (SD 26.7%)], followed by coanalgesic
drugs [mean 37.5% (SD 29.9%)] (Table 3). There was strong
consensus regarding the use of transmucosal fentanyl to treat
BTcP. Likewise, most respondents recommended oral and
intranasal fentanyl as their treatment of choice (Table 4).
Regarding the method used for dose calculation, more than
half of respondents (56.2%) preferred gradual dose adjust-
ment, irrespective of the basal opioid dose, while pain inten-
sity was the determining factor in dose titration (Table 5).
BTcP follow‑up
There was also broad agreement among participants (77.5%)
on the need to evaluate patients within 48–72 h after starting
BTcP medication. In addition, most (75.3%) believed that all
physicians involved in the patient’s care should be respon-
sible for follow-up. The most common reason for chang-
ing opioid medication was lack of effectiveness (56.2%),
followed by tolerability issues (39.3%). Furthermore, when
pain-unit experts were asked to estimate the percentage
of patients using ROOs incorrectly in the preceding year,
around 38% believed that more than 10% of BTcP patients
had misused ROOs due to abuse or over-use; while 65.2%
have underused these therapies (Fig. 1). Finally, around half
of the experts (52.8%) considered that their patients com-
plied with BTcP treatment.
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Table 1  Organizational aspects of pain units

Questions

What type of pain unit does your Hospital or healthcare department have? N (%)
 Level I (Pain management techniques) 9 (10.1%)
 Level II (Uni-disciplinary pain management unit) 40 (44.9%)
 Level III (Multidisciplinary pain management unit) 40 (44.9%)
Has the unit been accredited for pain management? N (%)
 Yes 40 (44.9%)
 No 49 (55.1%)
How many doctors work in your hospital’s pain unit? Mean (SD)
 Nº full-time…………………………… 1.6 (1.6)
 Nº part-time…………………………. 3.4 (2.1)
Which other healthcare professionals are involved in your pain unit? Mean (SD)
 Nurses 1.9 (1.2)
 Psychologists 0.6 (0.6)
 Pharmacists 0.3 (0.4)
 Others 1.8 (1.3)
Which medical specialties are included in the pain unit? N (%)
 Anesthesia 87(97.8%)
 Palliative care 7 (7.9%)
 Rheumatology 4 (4.5%)
 Neurosurgery 6 (6.7%)
 Rehabilitation 18 (20.2%)
 Traumatology 1 (1.1%)
 Primary care 17 (19.1%)
 Others 18 (20.2%)
What is the catchment area of your pain unit? N (%)
 < 50,000 inhabitants 2 (2.2%)
 From 50,000 to 100,000 inhabitants 8 (9%)
 From 100,000 to 200,000 inhabitants 21 (23.6%)
 From 200,000 to 300,000 inhabitants 16 (18%)
 > 300 000 inhabitants 42 (47.2%)
How many patients with chronic pain were seen in your pain unit last year (2015)? N (%)
 < 500 patients 3 (3.4%)
 From 500 to 1000 patients 12 (13.5%)
 From 1000 to 5000 patients 50 (56.2%)
 From 5000 to 10,000 patients 19 (21.3%)
 > 10,000 patients 5 (5.6%)
What percentage of patients with chronic pain had oncologic pain in your pain unit? N (%)
 < 10% 61 (68.5%)
 10–25% 25 (28.1%)
 26–50% 3 (3.4%)
What percentage of patients with oncologic pain had breakthrough pain (BTcP) in your pain unit? N (%)
 < 25% 25 (28.1%)
 > 75% 16 (18%)
 26–50% 21 (23.6%)
 51–75% 27 (30.3%)
Does your hospital have the following units or services? N (%)
 Medical oncology 84 (94.4%)
 Radiation oncology 51 (57.3%)
 Palliative care 72 (80.9%)

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Table 1  (continued)
Questions

 Hospital at Home Program 62 (69.7%)

Does your Hospital or healthcare department have a referral protocol for the pain unit? N (%)
 Yes 33 (37.1%)
 No 56 (62.9%)
Does your pain unit use interventional techniques to treat oncologic pain? N (%)
 Nerve block 73 (82%)
 Intrathecal pump placement 60 (67.4%)
 Medullar stimulators 45 (50.6%)
 Others 45 (50.6%)

BTcP breakthrough cancer pain, SD standard deviation

Table 2  Respondents’ opinion of risk factors for BTcP definition clearly states that BTcP episodes should occur
Risk factors for BTcP [Rated from 1 (highest risk) to 5 Mean (SD)
in the context of underlying background pain controlled by
(lowest risk)] strong opioids. It seems indisputable that BTcP episodes
occur in patients with stable baseline pain of moderate inten-
Locally advanced/aggressive tumor 2.0 (1.1) sity, adequately controlled with analgesia [16]. However, the
Metastatic tumor 2.3 (1.0)
analgesics used to treat baseline pain have been the source of
Metastasis with bone involvement 2.4 (1.2)
some controversy. Currently, BTcP drugs, and specifically
Combined chemotherapy and radiation therapy 4.1 (0.9)
new fentanyl preparations, are limited to patients already
Aggressive surgeries 4.3 (1.0)
receiving at least 60 mg/day of oral morphine equivalents
BTcP breakthrough cancer pain, SD standard deviation as maintenance therapy [17]. In addition, all the pivotal tri-
als involving ROOs have been conducted in opioid-tolerant
patients taking ≥ 60 mg/day of oral morphine equivalents for
Discussion background pain [18]. In the absence of clinical studies in
BTcP patients taking lower doses of strong or weak opioids,
To the best of our knowledge, this is the first study that eval- a panel of experts defined this entity as “a relevant change
uates the opinion of a panel of experts formed exclusively of in pain intensity in patients who receive an effective treat-
pain-unit specialists on the most important aspects of BTcP, ment with opioids, presumably in doses of at least 60 mg of
a major issue associated with cancer. oral morphine equivalents” [19]. Nevertheless, many experts
argue that the type of analgesia used for background pain
BTcP definition should not be included in the definition of BTcP, as a sig-
nificant percentage of cancer patients receive weak opioids,
The pain specialists polled strongly agreed with the first defi- such as tramadol, for their background pain in clinical prac-
nition of BTcP [1] but this was not unanimous. Portenoy’s tice [20]. A recent consensus study showed that only 30%
of the panel experts consider the use of opioid analgesics to

Table 3  Respondents’
estimation of the percentage
of BTcP patients that should
be treated with each type of
medication
Percentage of BTcP patients that should be Percentage of BTcP patients that should be treated with
treated with different therapeutic options, different medications, according to experts
according to experts
Therapeutic options: Mean (SD) (%) Pharmacological treatments options Mean (SD) (%)

Pharmacological treatment 77.0 (26.7) Rapid-onset of action opioids 77.0 (26.7)

with opioids
Adjuvant treatments 49.9 (29.7) Coanalgesic drugs 37.5 (29.9)
Interventional techniques 32.9 (27.1) Slow-onset of action opioids 30.5 (34.7)
Antalgic radiotherapy 24.0 (21.7) NSAIDs 20.4 (24.1)
Surgery 13.3 (16.8) Weak opioids 15.9 (19.9)

BTcP breakthrough cancer pain, SD standard deviation

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Table 4  Respondents’ preference regarding routes of administration BTcP diagnosis

and therapeutic options for BTcP treatment
Routes of administration: rated from one (most com- Mean (SD) Despite the lack of a validated tool for the diagnosis and
monly used) to five (least used) assessment of BTcP, the literature recommends the use of
 Oral transmucosal sublingual 1.8 (1.1)
the Davies’ algorithm [3], modified from the original pub-
 Transmucosal intranasal 2.2 (1.1)
lished in 2009 [2]. However, according to our survey, only
 Oral transmucosal non-sublingual 2.8 (1.3)
30.3% of pain-unit physicians use this algorithm as their
 Oral 4.4 (1.1)
gold standard. This lack of consensus among pain manage-
 Intravenous/subcutaneous 4.8 (1)
ment specialists may be caused by a lack of awareness of
this tool, although it could also be due to the complexity of
Therapeutic options: rated from (one most recom- Mean (SD)
mended) to seven (least recommended) BTcP [2]. Recent epidemiological studies have provided a
comprehensive characterization of BTcP episodes in terms
 Oral transmucosal fentanyl 1.6 (1.0) of duration, intensity, frequency and predictability in a
 Intranasal transmucosal fentanyl 1.6 (0.7) European population, showing that this is a very hetero-
 Immediate release oxycodone 5.1 (2.1) geneous condition characterized by both inter- and intra-
 Immediate release morphine 5.4 (2.1) individual variability [3, 23]. This evidence suggests that
 Parental opioids 5.4 (2.0) diagnosis of BTcP requires a more comprehensive assess-
 Oral methadone 7.2 (1.3) ment than the Davies’ algorithm. In fact, recent evidence
 Hydromorphone 7.3 (1.2) shows that it has limited sensitivity to detect BTcP, and
BTcP breakthrough cancer pain, SD standard deviation
that a comprehensive clinical assessment is preferred [24].
A recent study to assess the level of agreement among
physicians involved in cancer management in Spain [21]
Table 5  Importance given by pain management specialists to differ- showed that they failed to reach consensus on an impor-
ent factors involved in dose calculation
tant criterion in the diagnostic algorithm of BTcP, namely:
Features to consider during dose calculation, rated from Mean (SD) ‘‘Background pain is present 12 h/day during the previous
one (most important) to five (least important)
week”, demonstrating discrepancies among various medical
Pain intensity 1.5 (0.8) specialties in Spain. All this evidence suggests that BTcP
Frequency of BTcP episodes 2.8 (1.2) diagnosis in the Spanish health care system does not follow
Duration of BTcP episodes 3.5 (1.1) a standard protocol, and this may lead to its underdiagnoses
Adverse events 3.6 (1.2) and suboptimal treatment.
Patient functionality 3.6 (1.4)

BTcP breakthrough cancer pain, SD standard deviation

BTcP treatment

Regarding the medication to be used to manage BTcP,

Fig. 1  Respondents’ estimation of the percentage of patients with
an inappropriate use of rapid-onset opioids (ROOs). Around 38% of
respondents believed that more than 10% of BTcP patients had mis-
used ROOs due to ab over-use, while 65.2% though that more than
10% of BTcP patients had underused ROOs
manage background pain to be an essential feature of BTcP
[21, 22].
respondents agreed that strong opioids should be the first
option. According to the experts, the ideal treatment should
be ROOs that provide optimal analgesia and rapid onset of
action. The support for ROOs by Spanish pain experts con-
firms the growing consensus in favor of these treatments
among most specialists [21, 22] and leading medical socie-
ties [12, 13].
In particular, most participants in this survey were in
favor of using oral and intranasal transmucosal fentanyl for
BTcP treatment versus immediate-release oral morphine,
which has traditionally been the first-line rescue medication
[25]. Accumulated evidence shows that transmucosal fenta-
nyl formulations provide more effective and rapid analgesia
in comparison with oral morphine in the treatment of BTcP
[11, 26]. For adequate BTcP analgesia, it is also important
for opioids to be titrated over time to meet the needs of
each patient [27]. In this regard, real-life data from differ-
ent European countries [28] have shown that transmucosal

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fentanyl formulations can be successfully titrated in most
cancer patients regardless of individual characteristics or
geographical setting. This finding indicates that transmu-
cosal fentanyl formulations not only provide adequate BTcP
analgesia while minimizing the risk of side effects, but also
can be successfully titrated in real-life conditions to provide
individually tailored BTcP treatment.
BTcP follow‑up
Most respondents agreed that all physicians involved in
the patient’s care should be responsible for follow-up. In
addition, consensus was strong regarding the need for early
assessment (within 48–72 h) after treatment initiation. This
is echoed in the literature, where multidisciplinary Spanish
cancer pain experts reached a strong consensus regarding
the need for early and comprehensive assessment after BTcP
treatment initiation [21, 22].
One particularly important finding in the present study
was that a high percentage of physicians polled believed
that their BTcP patients underused ROOs. To the best of
our knowledge, this is the first study to report the opinion of
pain management specialists on ROOs underuse by BTcP
patients in routine clinical practice in Spain, and is consist-
ent with a growing body of evidence that a high proportion
of BTcP patients are under-treated [6, 14]. However, under-
treatment of BTcP patients in Spain and its possible causes
have not hitherto been investigated in the literature. Recent
data describe an important variability in the use of opioid
analgesics worldwide [29]. Opioid abuse is a public health
problem in the USA that has been extensively described in
the literature [30]. In Europe, however, stricter regulation
might prevent misuse, but might also limit the legitimate
use of opioids [29], and therefore lead to under-treatment of
pain. There are many other possible causes for the subop-
timal management of BTcP, such as an incorrect diagnosis
and assessment of the pain, patient distrust of opioids, or
physicians’ reluctance to prescribe opioids [4, 7]. In addi-
tion, cultural or educational factors might affect the use of
opioids by patients [31]. For instance, a cancer patient who
has concerns and misconceptions about pain (considers pain
to be inevitable, uncontrollable, or believes that increasing
pain indicates disease progression) will be reluctant to report
pain and take opioids.
Conclusion
Overall, the results of our real-world study show broad
agreement among pain-unit specialists on many impor-
tant aspects of BTcP management, such as its key charac-
teristics, their preferences for ROOs for BTcP treatment,
or the need for early follow-up (48–72 h) after treatment
initiation. However, the present study also revealed a lack
of consensus in the use of the Davies’ Adapted Diagnos-
tic Algorithm for BTcP diagnosis, suggesting that BTcP
diagnosis does not follow a standard protocol in Span-
ish pain units. Another particularly important finding is
that a high percentage of pain-unit physicians believe that
their patients underuse ROOs, suggesting that many cancer
patients in Spain could receive suboptimal analgesia for
their BTcP episodes. In summary, our results highlight the
need to widen the consensus among pain-unit physicians
regarding the diagnostic method of choice for BTcP and
pave the way for new studies to assess the existence and
causes of under-treatment of BTcP patients in Spain.
Acknowledgements  We would like to thank the following research-
ers for their contribution to this study: Hermann Ribera, María José
Pampin Conde, Jorge Luis Sobrino Ramallo, Joan Coma, María de
la Luz Cánovas Martínez, Daniel Samper Bernal, Sergi Suarez Diaz,
Elvira Pelet Pascual, José Santamaría, Enrique Latorre Marqués, Jenaro
Mañero Rey, Margarita López Rouco, Ignacio Velázquez, Jose Luis
Cid Calzada, Francisco Javier Robaina Padrón, Inmaculada Herrador
Montiel, Rafael de Alba Moreno, Vicente de Sanctis, Manuel Ruiz
Castro, Josefina Castillo Rodríguez, Luis Fuentetaja Martin Portugués,
Juanma Mercado, Mar Domínguez, Ignacio Javier Hernández Ferre-
ras, Concepción Pérez Hernández, Cristina del Pozo Martin, Manuel
Sánchez del Águila, Nacho Calvo, Ángel Martínez Navas, Francisco
Heredia, Manuel López Rodríguez, Fernando Neira Reina, Rosa Zueras
Batista, Agustín Gerri Cebollada, José Miguel Esparza, Ángeles Canós,
Juan Manuel Vaca, Lourdes Marugan, Emilio Miguel Bronte Borraz,
Juan Carlos Carrión Pareja, Antonio Pajuelo Gallego, Dolores Bed-
mar Cruz, Antonio Carrascosa Fernandez, Francisco Sánchez Montero,
David Abejón González, Rafael Salazar, Juan Caballero Callejas, Jesus
Maldonado Contreras, Fernando Remartínez, Juan Carlos de la Pinta,
Antonio Alcántara Montero, Martín Arcas Molina, María López
Gómez, Pedro José Moñino Ruiz, Estrella Uriarte Brizuela, Jose
Antonio Sánchez Tirado, Rosa María Albores Albores, Pere Ortells
Nebot, Javier de Andrés Ares, Mª Dolores Rodrigo Royo, Antonio
Montero Matamala, Jordi Guitart, Victoria Ribera, Jose Gil Fuentes
Bellido, Vicente Domingo, Inmaculada Muro Castillo, Aurora de la
Iglesia, Francisco Leal Quiñones, Cristina Martin, José Javier Carcel-
ler Ruiz, Consuelo Nieto Iglesias, Carlos Tornero Tornero, Juan Pérez
Cajaraville, Mercedes Mozas Calabaza, Alfonso Diz Villar, Marta del
Valle Hoyos and Manuel Gutiérrez Ramírez. The authors thank Lucía
Perez at MSC (Valencia, Spain) for editorial support in writing of this
manuscript. All authors revised the manuscript versions and approved
the final draft.
Funding  The Relevium project was sponsored by the Grupo de trabajo
de dolor oncológico of the SED (Sociedad Española de Dolor). Takeda
pharmaceutics sponsored the creation and maintenance of the study´s
on-line database, but was not involved in data collection, analysis and
conclusions of the study.
Compliance with ethical standards 
Conflict of interest  The following authors declare potential conflicts
of interest for individual activities for the industry: Villegas Estévez
F. has received payments for consultancies and lecture fees from
Kyowa kirin, Gebro pharma, Grünenthal, Ferrer and Mylan. López
Alarcón M.D. has received payments for consultancies and lecture
fees from Kyowa kirin, Takeda, Gebro pharma, Lab Esteve, Teva and
13
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Clinical and Translational Oncology

Grünenthal. Mayoral V. has received payments for consultancies and 11. Zeppetella G, Ribeiro MD. Opioids for the management of
lecture fees from Menarini, Pfizer, Grünenthal, Mundipharma, Takeda breakthrough (episodic) pain in cancer patients. Cochrane Data-
y Kyowa Kirin. Madariaga M. has received lecture fees from Kyowa base Syst Rev. 2006;1:CD0043. https​://doi.org/10.1002/14651​
kirin, Grünenthal, Mundipharma, Ferrer and Medtronic. Carregal A. 858.CD004​311.pub2.
has received payments for consultancies and lecture fees from Take- 12. Jara C, Del Barco S, Gravalos C, Hoyos S, Hernandez B, Munoz
da, Gebro pharma, Lab Esteve, Teva, Grünenthal and Kyowa kirin. M, et al. SEOM clinical guideline for treatment of cancer pain
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