See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/323400535

Treating breakthrough pain in oncology

Article  in  Expert Review of Anticancer Therapy · February 2018

DOI: 10.1080/14737140.2018.1443813

CITATIONS READS

0 96

1 author:

Sebastiano Mercadante
La Maddalena Cancer Center
478 PUBLICATIONS   14,145 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

At the moment we are assessing the minimal differences perceived by cancer patinets in symptom intensity.In september we are ready to start with a nMinimal
intensity - Low doses of methadone View project

IOPS Study View project

All content following this page was uploaded by Sebastiano Mercadante on 21 April 2018.

The user has requested enhancement of the downloaded file.

 Expert Review of Anticancer Therapy

ISSN: 1473-7140 (Print) 1744-8328 (Online) Journal homepage: http://www.tandfonline.com/loi/iery20

Treating breakthrough pain in oncology

Sebastiano Mercadante

To cite this article: Sebastiano Mercadante (2018) Treating breakthrough pain in oncology, Expert
Review of Anticancer Therapy, 18:5, 445-449, DOI: 10.1080/14737140.2018.1443813

To link to this article: https://doi.org/10.1080/14737140.2018.1443813

Accepted author version posted online: 26

Feb 2018.
Published online: 16 Mar 2018.

Submit your article to this journal

Article views: 17

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=iery20
EXPERT REVIEW OF ANTICANCER THERAPY, 2018
VOL. 18, NO. 5, 445–449
https://doi.org/10.1080/14737140.2018.1443813

REVIEW

Treating breakthrough pain in oncology

Sebastiano Mercadante
Anesthesia and Intensive Care &Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Palermo, Italy

ABSTRACT ARTICLE HISTORY

Introduction: Breakthrough cancer pain (BTcP) is an episode of severe intensity in patients receiving an Received 13 November 2017
adequate treatment with opioids able to provide at least mild analgesia. BTcP is a heterogeneous Accepted 19 February 2018
condition as episodes vary between individuals. The aim of this article is to review the pharmacologic KEYWORDS
options for the management of BTcP. Breakthrough pain; fentanyl
Areas covered: Recent reviews revealed that transmucosal preparations of fentanyl provided superior preparations; oral opioids;
and more rapid pain relief as compared to placebo and oral morphine within the first 30 min after cancer pain
dosing. Few comparison studies among fentanyl products have been performed. Although dose
titration has been recommended for years, a meaningful dosing, according to the level of opioid
tolerance, may enhance the advantages of such products
Expert commentary: BTcP represents a relevant problem reported by many cancer patients despite
receiving regular use of opioids. Different modalities of pharmacological interventions are available. In
comparison with oral opioids, fentanyl preparations appear to have a short onset and offset of analgesic
effect, fitting the temporal characteristics of BTcP. Further studies are warranted to assess the net
benefit of these drugs to assist decision-making by patients, clinicians, and payers, according to
individual clinical conditions.

1. Introduction 1.1. Characteristics of breakthrough pain

BTcP is defined as a transitory increase in pain to greater
than moderate intensity which occurs on a background pain
considered to be acceptable for most hours of the day [1].
Patients with pain that is otherwise well controlled by an
analgesic drug may experience painful episodes of short
duration that may be highly distressing or compromise
function. The prevalence of BTcP has been variably reported
in literature, ranging in 40–80% of cancer patients, depend-
ing on the setting, the stage of disease, and diagnostic
criteria [2,3]. After 25 years, the characteristics of BTcP are
better known [4]. To label BTcP, patients should be receiv-
ing a stable opioid therapy able to maintain baseline pain
controlled over some period of time [5,6]. BTcP may be
precipitated by an event (predictable BTcP), or may occur
spontaneously (unpredictable or idiopathic), without an
identifiable cause or precipitating event [5,7–11]. For exam-
ple, incident-type BTcP is triggered by a well identifiable
event such as movement-induced bone pain due to meta-
static disease, as well as swallow-induced oropharyngeal
pain from mucositis
In contrast, BTcP related to insufficient opioid therapy,
particularly at the end of a dosing interval (so-called end-of-
dose failure), should not be categorized as BTcP [4–6]. Pain
fluctuation may be also encountered in patients who are not
receiving an opioid, may share characteristics in common with
acute pains that occur during opioid therapy.
In general, BTcP can be classified in two big distinct pictures.
In the spontaneous-type BTcP, there are no specific triggers
and is unpredictable. The onset and duration of this subtype
of BTcP is generally longer [7–11]. In incident-type pain, there
is a recognized factor precipitating the event (predictable).
Although, 3–4 episodes per day are commonly considered
acceptable whether most hours of the day are covered by an
adequate pain control [12], there are some episodes, for exam-
ple, incident pain due to bone metastases, that can occur
more frequently. In this case, the treatment should be focused
on a compromise between activity and background analgesia.
Incident-type BTcP has a shorter time to peak intensity and a
shorter time duration. These episodes are potentially self-
limited by resting, although pain may persist after stopping
activity for an unpredictable time. For this reason, there is a
relevant interference with daily living, as patients avoid trig-
gering BTP, limiting their activity or are forced to find indivi-
dual strategies to prevent the occurrence of BTcP.
The characteristics of BTcP have been recently examined
in large sample of patients. More than 80% of patients with
BTcP reported a significant negative impact in everyday life.
The mean number of episodes was 2.4/day, and mean
intensity of BTcP was 7.4 on a numerical scale 0–10. The
onset of BTP was more often short, less than 10ʹ in more
than 1/3 of patients. Patients with predictable BTcP
reported a fast onset of BTcP. The mean duration of

CONTACT Sebastiano Mercadante terapiadeldolore@lamaddalenanet.it; 03sebelle@gmail.com Pain Relief and Palliative Care Unit, La Maddalena Cancer
Center, Via San Lorenzo 312, 90146 Palermo, Italy
© 2018 Informa UK Limited, trading as Taylor & Francis Group
446 S. MERCADANTE
untreated episodes of BTP was 30–40 min [8]. These char-
acteristics may change during the course of disease [7].
2. Treatment OF BTcP
There are various options to treat BTcP, including pharmaco-
logical and non-pharmacological treatments. The principal
pharmacological treatment is based on the administration of
opioids as needed.
2.1. Oral opioids
For the management of BTcP, immediate release formulations
of oral opioids are available. For many decades, oral opioids
have been the mainstay approach for the management of
BTcP. Oral morphine has been traditionally given in doses
proportional to opioid doses used for background analgesia
[13], NICE guidelines suggest to use oral morphine as first-line
drug [14]. Oral opioids, however, have onset and duration of
action not suitable for treating many episodes of BTcP, which
are characterized by a typical temporal pattern. From the
pharmacokinetic point of view, there is a poor correlation
between the analgesic effect of oral opioids with the dynamics
of a typical BTcP episode [15]. It is relevant to underline that
BTcP duration is often limited in time (about 30–40ʹ), and the
analgesic effect with oral opioids is expected 30–45 min when
most episodes spontaneously evanish. Curiously, no study has
been performed with oral opioids in the management of BTcP,
unless in comparison studies of fentanyl preparations.
Although intravenous morphine given in doses proportional
to basal opioid regimen provides a rapid and effective analge-
sia, within 5–15 min, it is not feasible for most patients [16].
2.2. Transmucosal fentanyl preparations
The best option could be administering a drug providing
analgesia within 10ʹ persisting for about 1 h to cover the
temporal pattern of most episodes of BTcP. In these circum-
stances, the speed of analgesic onset is crucial for an effective
pain management. In the last 10 years, different technologies
have been developed to provide fast pain relief, based on a
common drug such as fentanyl, delivered by noninvasive
routes. Fentanyl is a potent and strongly lipophilic drug able
to pass through the mucosa and then across the blood–brain
barrier to provide fast analgesia. Existing literature support the
superior pain relief with fentanyl products as compared to
placebo or oral morphine within in the first 30 min after
dosing [17–19]. Each transmucosal preparation of fentanyl
has its particularities and availabilities. All these preparations
should be given in opioid tolerant patients receiving at least
60 mg or oral morphine equivalents.
2.2.1. Oral transmucosal preparations
2.2.1.1. Oral transmucosal fentanyl citrate (OTFC). OTFC
consists of a fentanyl impregnate sweetened lozenge on a
plastic handle. The lozenge should be gently rubbed against
the buccal mucosa until it has completely dissolved. This
process requires about 15 min when appropriately used [20].
Absolute availability is about 50%, although the percentage
absorbed by mouth and immediately available for treating
BTP is about 25%, as the rest is swallowed [21]. OTFC has
demonstrated to have a fast effect and to be more effective
than placebo or oral morphine for treating BTcP [22–24].
Safety profile seems to be acceptable even in long-term use
[25]. OTFC, formulated as self-administration of a solid drug
matrix on a handle, however, requires patient discipline and
focus, which may compromise the compliance, for example, in
patients with weakness, a common symptom in advanced
stage of disease. Indeed, the use of this product can be dis-
continued when sufficient analgesia is produced as the unit is
easily removed from the mouth with the handle. Such flex-
ibility is not available with other fentanyl products. This is an
off-label use that has never assessed scientifically.
2.2.1.2. Fentanyl buccal tablet (FBT). FBT is a second gen-
eration of fentanyl delivery system, formulated to provide
rapid-onset analgesia by enhancing fentanyl absorption across
the buccal mucosa. Oravenescent technology produces an
effervescent reaction that liberates carbon dioxide in the buc-
cal cavity. This reaction causes an initial decrease of pH, which
facilitates solubilization. The subsequent release of carbon
dioxide increases the local pH, which optimizes permeation
of unionized fentanyl across the buccal mucosa [26]. The
availability of FBT is estimated to be 65%. Short-term, rando-
mized, controlled, clinical studies in patients with cancer pain
have shown the efficacy of FBT in the management of BTcP in
comparison with placebo and oral morphine. The efficacy was
also confirmed in long-term studies on the safety and toler-
ability of FBT [27–29].
2.2.1.3. Sublingual fentanyl (SLF). SLF is formulated as a
rapidly disintegrating tablet system containing a mixture of
carrier particles coated with active drug particles and contain-
ing a mucoadhesive agent. The bioavailability of SLF is esti-
mated to be about 70% [17]. SLF has demonstrated to have a
fast effect and to be more effective than placebo for treating
BTP. Safety profile seems to be acceptable and was confirmed
in long-term studies [30–32].
2.2.1.4. Fentanyl buccal soluble film (FBSF). Other buccal
preparations with similar fentanyl availability are a sublingual
spray and buccal soluble film, characterized by a bio-erodible
mucoadhesive delivery technology [33]. FBSF presents fenta-
nyl in a layer that adheres to the inside of the patient’s cheek.
An outer layer isolates the fentanyl-containing layer from
saliva to minimize the quantity of fentanyl that is swallowed
in the saliva. FBSF was more effective than placebo for the
management of BTP, and tolerability was good [34].
2.2.2. Nasal transmucosal preparations
When the buccal mucosal damages or salivary dysfunction the
intranasal administration of fentanyl may have some advantages,
for example, in patients with mucositis or local infection. The
development of an intranasal administration of fentanyl emerged
as an effective method of administration. In the internal nose, the
surface area of the nasal mucosa is large to allow an appropriate
absorption of liposoluble drugs. The availability is high (65–90%),

depending on type of preparation, and the onset of action is very
short (5–10ʹ). Two formulations of nasal fentanyl have been devel-
oped, an aqueous solution (INFS) as well as a pectin-based drug
delivery system in the form of a gel designed to be applied to
mucosal surfaces to optimize absorption (FPNS) [17]. The pectin-
based drug delivery system has been designed to gel when
applied to mucosal surfaces to optimize absorption, giving a
rounded pharmacokinetic profile compared with the sharp profile
of INFS, attenuating the peak plasma concentration, with an
availability of about 65% [35]. INFS and FPNS provide the fastest
method of analgesia for BTcP. Both preparations were found more
effective than placebo, and in comparison, studies INFS and FPNS
were more effective in comparison with OTFC and oral morphine,
respectively [36–39]. Long-term studies confirmed the tolerability
and efficacy of nasal fentanyl products [40,41].
3. Expert commentary
For the management of BTcP we need drugs able to provide
analgesia from 5–10 to 60 min. Until a decade ago, immediate
release oral opioids have been given in doses proportional to
opioid doses used for background analgesia (about 1/6) [13].
Recent NICE guidelines suggest to use oral morphine as first
choice [14], according to the low differences reported 30 min
after administration, in comparison studies with fentanyl pro-
ducts. Pharmacokinetic studies have suggested a poor correla-
tion of their analgesic effect with the dynamics of a typical BTP
episode [15]. It is likely that oral morphine could provide
analgesia from 30 to 240 min, a time interval that does not
fit the temporal pattern of BTcP. BTcP duration is often limited
in time (about 340 min). This means that when oral morphine
may produce analgesia, most episodes may spontaneously
evanish, independently from the administration of the drug,
which however may maintain its unneeded effect for about
four hours. Indeed, oral morphine, despite its traditional use of
more than 50 years, has never assessed as BTcP medication, or
compared with placebo with an appropriate design. On the
contrary, when compared with fentanyl products, it resulted to
have a longer onset and to be less effective and performed
slightly better than placebo [4,42]. With most BTP
episodes peaking in intensity within a few minutes and lasting
for 30–60 min, the speed of analgesic onset is crucial for an
effective pain management. Oral opioids may still have an
indication, for example in patients with predictable BTcP epi-
sodes, given preemptively 30 min before starting activity, or in
patients presenting slower onset of pain peaks. Finally,
patients’ preference may be determinant.
Different fentanyl preparations exist and each of them
has its preclusive specificity in terms of use, availability,
strengths, availability. Thus, the choice should be based on
the individual conditions either for the anatomic site to be
used to give the drugs transmucosally. When a switch to
another fentanyl product is necessary, due to changes in
the local condition (mouth or nasal cavity damages), no
information about equipotency among the various formula-
tion exists. Ideally, taking into consideration the initial
strength proposed for initial therapy in patients tolerant to
60 mg or oral morphine, we could assume that the multiple
doses would be similarly equivalent. For instance, INFS and
EXPERT REVIEW OF ANTICANCER THERAPY 447
FPNS provided a similar analgesic profile in doses of 50 and
100 µg, and their multiples, respectively [43].
The choice of the dose of the fentanyl products to be
prescribed as needed remains controversial. In the initial com-
parative studies performed with an open phase of dose titra-
tion, effective doses were not associated with the basal opioid
regimen. According to this finding, a recommendation of
titrating the dose starting with the lowest dose available was
given. The reasons for these findings are not clearly explained
from a pharmacological point of view, considering that the
presence of tolerance should suggest a dose proportional to
those used for background analgesia. These data need an
accurate interpretation. In one of the controlled studies, a
relationship between dose and the fixed scheduled opioid
had been already found, and regular rescue dose was a mod-
erate predictor of the effective OTFC dose. Of interest, only
19% of the variability of the final dose of OTFC was explained
by basal doses of opioids, according to the low-R-square vale
of the model used [42]. Observations from data pooled from
trials of OTFC showed a statistically significant relationship
between the breakthrough dose and around-the-clock dose,
despite a relevant interindividual variability in patients’ dose
requirements for BP. The need to titrate has never been
determined on the basis of a comparison between titration
strategy and no titration strategy [44]. Indeed, dose titration
may make the practical use of fentanyl preparations difficult in
the daily activity, particularly at home or in outpatients. Most
patients may be reluctant to try the dose and avoid to use
these drugs, preferring, at the end, traditional oral dosing of
morphine. In subsequent studies, doses of fentanyl propor-
tional to the amount of opioids given for background pain
were effective and safe. In a recent study, dose titration
method was compared with the use of proportional doses.
The latter produced more effective analgesia and less drop-
outs, while being similarly safe, in patients receiving larger
doses of opioids for background analgesia [45]. Patients
receiving high doses of opioids as basal opioid regimen
should not be candidates for titration starting with the mini-
mal strength of fentanyl, as they are opioid-tolerant, and this
process would be time consuming. Thus, a reliable compro-
mise between the different opinions could be to start with
relatively higher doses of fentanyl in highly tolerant patients,
until more information will suggest the best strategy.
4. Conclusion
In this review, the possible options of a pharmacological
treatment of BTcP have been revised. While oral opioids
have been given for years, the evidence for this approach is
poor, as no paper has specifically assessed the efficacy of oral
opioids for BTcP. Fentanyl preparation provide rapid onset and
offset of analgesia and were tolerated. The efficacy of these
products has been confirmed in long-term studies.
Controversies exist on the dose to be used. Pioneer recom-
mendations suggested to titrate the dose starting with the
minimal dose. This observation is biased by several conceptual
weaknesses. The knowledge that patients have different levels
of opioid tolerance, according to their background opioid
therapy, suggests to use doses proportional to the basal
448 S. MERCADANTE
opioid regimen. Such approach has been proven to efficacious
and safe in several studies. Further studies should establish
the equivalence among the different fentanyl preparations,
whether the pharmacological treatment could be tailored
according to BTcP characteristics, and whether doses propor-
tional to basal opioid regimen could be universally used, as
most research on this issue come from few centers.
5. Five-year view
In the last 5 years, many developments have been done and
more data are available. New technologies are available to
provide rapid onset opioids, namely fentanyl preparations, in
different ways which may match patients’ needs. New data
also suggested a different approach in dosing these sub-
stances to improve prescription and make easy the use of
fentanyl. Large studies have been also performed providing
more epidemiologic data regarding the characteristics of BTcP,
which is fundamental for a tailored treatment.
Key issues
● The pharmacologic treatment of BTcP is based on the
administration of opioids with a short onset of action as
needed.
● Oral opioids may be useful in some specific circumstances,
when used pre-emptively or for episodes with longer onset
of action
● In most cases fentanyl products, having a rapid onset and
offset of action, fit the temporal pattern of most BTcP
episodes
● Data on equivalence dosing among the different products
have not explore appropriately
● It is likely that predictable doses, based on a proportion of
the daily opioi dose, is as effective as safe, and may improve
patients’ compliance, without adding serious risks.
Funding
This manuscript has not been funded.
Declaration of interest
S Mercadante reports declares work associated with Grunenthal, TEVA,
Molteni, Kyowa Kyrin, Takeda and Angelini. The author has no other
relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from those dis-
closed. Peer reviewers on this manuscript have no relevant financial or
other relationships to disclose.
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence
and characteristics. Pain. 1990;41:273–281.
•• This is the first study assessing and providing the initial defini-
tion of breakthrough pain.
2. Mercadante S. Breakthrough pain in cancer patients: prevalence,
mechanisms and treatment options. Curr Opin Anaesthesiol.
2015;28:559–564.
3. Deandrea S, Corli O, Consonni D, et al. Prevalence of breakthrough
cancer pain: a systematic review and a pooled analysis of published
literature. J Pain Symptom Manage. 2014;47:57–76.
4. Mercadante S, Cuomo A. Breakthrough cancer pain: ten
commandments. Value Health. 2016;19:531–536.
5. Davies AN, Dickman A, Reid C, et al. Science Committee of the
Association for Palliative Medicine of Great Britain and Ireland. The
management of cancer-related breakthrough pain: recommenda-
tions of a task group of the Science Committee of the Association
for Palliative Medicine of Great Britain and Ireland. Eur J Pain.
2009;13:331–338.
6. Mercadante S, Portenoy RK. Breakthrough cancer pain: twenty-five
years of study. Pain. 2016;157:2657–2663.
•• Authoritative review of the developments of BTcP along 25
years.
7. Mercadante S, Lazzari M, Reale C, et al. Italian Oncological Pain
Survey (IOPS): a multicentre Italian study of breakthrough pain
performed in different settings. Clin J Pain. 2015;31:214–221.
8. Mercadante S, Marchetti P, Cuomo A, et al. Breakthrough cancer
pain: preliminary data of the Italian Oncologic Pain Multisetting
Multicentric Survey (IOPS-MS). Adv Ther. 2017;120–135.
• The largest study exploring the characteristics of BTcP.
9. Haugen D, Hjermstad M, Hagen N, et al. Assessment and classifica-
tion of cancer breakthrough pain: a systematic literature review.
Pain. 2010;141:476–482.
10. Hjermstad MJ, Kaasa S, Caraceni A, et al. Characteristics of break-
through cancer pain and its influence on quality of life in an
international cohort of patients with cancer. BMJ Support Palliat
Care. 2016;344–352.
11. Davies A, Buchanan A, Zeppetella G, et al. Breakthrough cancer
pain: an observational study of 1000European oncology patients. J
Pain Symptom Manage. 2013;46:619–628.
12. Portenoy RK, Payne D, Jacobson P. Breakthrough pain: character-
istics and impact in patients with cancer pain. Pain.
1999;81:129–134.
13. Hanks GW, De Conno F, Cherny N, et al. Morphine and alternative
opioids in cancer pain: the EAPC recommendations. Br J Cancer.
2001;587–593.
14. www.nice.org.uk/cg140
15. Zeppetella G. Dynamics of breakthrough pain vs pharmacokinetics
of oral morphine: implications for management. Eur J Cancer Care.
2009;331–337.
• Nice paper assessing the drug pharmacokinetics and the tem-
poral pattern of BTcP.
16. Mercadante S. Intravenous morphine for management of cancer
pain. Lancet Oncol. 2010;11:484–489.
17. Mercadante S. Pharmacotherapy for breakthrough cancer pain.
Drugs. 2012;181–190.
18. Jandhyala R, Fullarton JR, Bennett MI. Efficacy of rapid-onset oral
fentanyl formulations vs. oral morphine for cancer-related break-
through pain: a meta-analysis of comparative trials. J Pain
Symptom Manage. 2013;573–580.
19. Zeppetella G. Evidence-based treatment of cancer-related break-
through pain with opioids. J Natl Compr Canc Netw. 2013;S37–S43.
20. Aronoff GA, Brennan MJ, Pritchard DD, et al. Evidence-based oral
transmucosal fentanyl citrate (OTFC) dosing guidelines. Pain Med.
2005;305–314.
21. Schug SA, Ting S. Fentanyl formulations in the management of
pain: an update. Drugs. 2017;77:747–763.
22. Farrar J, Cleary J, Rauck R, et al. Oral transmucosal fentanyl citrate: a
randomized, double-blinded, placebo-controlled trial for treatment
of breakthrough pain in cancer patients. J Natl Cancer Inst.
1998;90:611–616.
23. Portenoy RK, Payne R, Coluzzi P, et al. Oral transmucosal fenta-
nyl citrate (OTFC) for the treatment of breakthrough pain in
cancer patients: a controlled dose titration study. Pain.
1999;79:303–312.

24. Christie J, Simmonds M, Patt R, et al. Dose-titration multicenter
study of transmucosal fentanyl citrate for the treatment of break-
through pain in cancer patients using transdermal fentanyl for
persistent pain. J Clin Oncol. 1998;16:3238–3245.
25. Payne R, Coluzzi P, Hart L, et al. Long-term safety of transmucosal
fentanyl citrate for breakthrough cancer pain. J Pain Symptom
Manage. 2001;115:575–583.
26. Blick S, Wagstaff AJ. Fentanyl buccal tablets in breakthrough pain
in opioid-tolerant patients with cancer. Drugs. 2006;66:2387–2393.
27. Portenoy RK, Taylor D, Messina J, et al. A randomized,
placebo-controlled study of fentanyl buccal tablet for breakthrough
pain in opioid-treated patients with cancer. Clin J Pain. 2006;5:805–811.
28. Slatkin NE, Xie F, Messina J, et al. Fentanyl buccal tablet for relief of
breakthrough pain in opioid-tolerant patients with cancer-related
chronic pain. J Support Oncol. 2007;155:327–334.
29. Weinstein SM, Messina J, Xie F. Fentanyl buccal tablet for the
treatment of breakthrough pain in opioid-tolerant patients with
chronic cancer pain: a long-term, open-label safety study. Cancer.
2009;2571–2579.
30. Lennernas B, Frank-Lissbrant I, Lennernas H, et al. Sublingual
administration of fentanyl to cancer patients is an effective treat-
ment for breakthrough pain: results from a randomized phase II
study. Palliat Med. 2010;286–293.
31. Rauck R, Tark M, Reyes E, et al. Efficacy and long-term tolerability of
sublingual fentanyl orally disintegrating tablet in the treatment of
breakthrough cancer pain. Curr Med Res Opin. 2009;2877–2885.
32. Nalamachu SR, Narayana A, Janka L. Long-term dosing, safety, and
tolerability of fentanyl buccal tablet in the management of
noncancer-related breakthrough pain in opioid-tolerant patients.
Curr Med Res Opin. 2011;751–760.
33. Vasisht N, Gever LN, Tagarro I, et al. Single-dose pharmacokinetics
of fentanyl buccal soluble film. Pain Med. 2010;11:1017–1023.
34. Rauck R, North J, Gever LN, et al. Fentanyl buccal soluble film (FBSF)
for breakthrough pain in patients with cancer: a randomized,
double-blind, placebo-controlled study. Ann Oncol.
2010;21:1308–1314.
35. Watts P, Smith A. PecSys: in situ gelling system for optimised nasal
drug delivery. Expert Opin Drug Deliv. 2009;6:543–552.
View publication stats
EXPERT REVIEW OF ANTICANCER THERAPY 449
36. Kress HG, Ororiska A, Kaczmarek Z, et al. Efficacy and tolerability of
intranasal spray 50 to 200µg for breakthrough pain in patients with
cancer: a phase III, multinational, randomized, double-blind, pla-
cebo-controlled, crossover trial with a 10-month, open-label exten-
sion treatment period. ClinTher. 2009;31:1177–1191.
37. Portenoy RK, Burton AW, Gabrail N, et al. A multicenter,
placebo-controlled, double-blind, multiple-crossover study of fen-
tanyl pectin nasal spray in the treatment of breakthrough cancer
pain. Pain. 2010;41:617–624.
38. Davies A, Sitte T, Elsner F, et al. Consistency of efficacy, patients
acceptability, and nasal tolerability of fentanyl pectin nasal spray
compared with immediate-release morphine sulphate in break-
through cancer pain. J Pain Symptom Manage. 2011;41:358–366.
39. Mercadante S, Radbruck L, Davies A, et al. A comparison of intra-
nasal fentanyl spray with oral transmucosal fentanyl citrate for the
treatment of breakthrough cancer pain: an open-label, rando-
mized, crossover trial. Curr Med Res Opin. 2009;2805–2815.
40. Portenoy RK, Raffaeli W, Torres L, et al. Long-term safety, tolerabil-
ity, and consistency of effect of fentanyl pectin nasal spray for
breakthrough cancer pain in opioid-tolerant patients. J Opioid
Manage. 2010;6:319–328.
41. Mercadante S, Vellucci R, Cuomo A, et al. Long-term efficacy and
tolerability of intranasal fentanyl in the treatment of breakthrough
cancer pain. Support Care Cancer. 2015;23:1349–1354.
42. Mercadante S. The use of rapid onset opioids for breakthrough cancer
pain: the challenge of its dosing. Crit Rev Oncol Hematol.
2011;80:460–465.
43. Mercadante S, Prestia G, Adile C, et al. Intranasal fentanyl versus
fentanyl pectin nasal spray for the management of breakthrough
cancer pain in doses proportional to basal opioid regimen. J Pain.
2014;602–607.
44. Mercadante S. Breakthrough pain: on the road again. Eur J Pain.
2009;13:329–330.
45. Mercadante S, Gatti A, Porzio G, et al. Dosing fentanyl buccal tablet
for breakthrough cancer pain: dose titration versus proportional
doses. Curr Med Res Opin. 2012;28:963–968.
• The first study comparing two different approaches for fenta-
nyl dosing.