Ò
PAIN 151 (2010) 565–566
Commentary
Fentanyl for breakthrough cancer pain – what’s new?
Approximately two-thirds of patients with cancer pain suffer
from breakthrough pain (BTCP), which is associated with high pain
intensity, impaired daily functioning and poor quality of life [11].
Despite recent advances in treatment, BTCP remains under-recog-
nized and inadequately managed. Treatment with conventional
opioids, such as morphine or oxycodone, on an as-needed basis is
limited by slow onset of analgesia and long duration of action,
when compared to the time profile of BTCP. To address these lim-
itations, several transmucosal formulations of fentanyl have been
developed to produce a compound with suitable pharmacokinetic
and pharmacodynamic properties for the treatment of BTCP. It
has also been suggested that for BTCP, inhaled fentanyl might pro-
vide even faster pain relief than transmucosal formulations [4,5].
In this issue of Pain, Portenoy et al. [10] report the results of a
multi-center, randomized, double-blind, crossover study to assess
the efficacy and tolerability of a new formulation, fentanyl pectin
nasal spray (FPNS) for BTCP. Patients diagnosed with cancer taking
60 mg or more of oral morphine equivalent for background pain
and experiencing one to four BTCP episodes per day were eligible
for the study. The authors used a modified enriched enrolment
withdrawal design to identify a population of patients who re-
sponded to FPNS. The responders then entered a double-blind
phase during which they were treated for 10 BTCP episodes with
either an effective dose of FPNS or placebo, in randomized order.
The results show that FPNS improved the mean-summed pain
intensity difference at 30 min (SPID30), which was the primary
end-point of the study. Statistically significant differences were
also observed in several secondary end-points, from 5 or 10 min
onwards after FPNS administration when compared to placebo,
and a clinically meaningful pain reduction defined by a P2-point
reduction in pain intensity was present from 10 min in FPNS-trea-
ted episodes. Approximately 70% of patients were satisfied or very
satisfied with the use of FPNS.
The question remains, what is the novelty value of these find-
ings? It has already been shown that oral and nasal transmucosal
fentanyl formulations are efficacious in the treatment of BTCP,
when compared to placebo, and they are well tolerated by patients
[3,7,12]. Furthermore, oral transmucosal fentanyl has been shown
to be superior to morphine in the treatment of BTCP [1]. Thus, the
main finding of the study, efficacy of FPNS in the treatment of BTCP
over placebo, was actually as expected and holds little novelty va-
lue. In their discussion, the authors emphasized the speed of the
onset of FPNS analgesia. It is noteworthy, however, that the study
was not designed to compare the speed of analgesia of one trans-
mucosal fentanyl product with another but to assess the efficacy
over placebo. The fact that that transmucosal fentanyl acts more
rapidly than placebo is not surprising [3,7,12].
Placebo response was high in the study. Approximately 90% of
BTCP episodes treated with FPNS and 80% of those treated with
0304-3959/$36.00 Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2010.08.026
www.elsevier.com/locate/pain
placebo did not require rescue medication. This is understandable
as many BTCP episodes may resolve relatively quickly with no
treatment. To be able to fully understand the relationship of the
pharmacokinetic and pharmacodynamic profile of FPNS with the
temporal characteristics of BTCP, it will be necessary to determine
plasma fentanyl concentrations. It has been argued that arterial
plasma samples may be needed to characterize the pharmacoki-
netics of nasal transmucosal administration of fentanyl, as there
is a significant arterio-venous difference in early plasma concen-
trations [9]. However, the determination of arterial fentanyl con-
centrations in connection with BTCP and FPNS would have made
the conduct of the study very difficult, if not impossible. It should
also be noted that the analgesic effects of FPNS cannot be reliably
assessed in BTCP as the pain may peak prior to the onset and re-
solve before the end of the fentanyl action [11]. In procedural mod-
els of pain, intranasal fentanyl doses of 75–200 lg have been
associated with onset of analgesia at 6–8 min with duration of
47–89 min [2].
We have some reservations also concerning the modified en-
riched enrolment randomized withdrawal design employed in
the study. This design has been increasingly used in efficacy stud-
ies of opioid analgesics, including rapid short-acting fentanyl for-
mulations, due to the benefits in demonstrating efficacy. The
design is not, however, entirely without flaws [6]. One of the major
problems in the present study was the risk of carry-over effects,
which may reduce the validity and reliability of the results. In
the present study the patients were instructed to keep a 4-h
interval between the doses. Because the elimination half-life of
intranasal fentanyl has varied between 89–179 min [2], the risk
of carry-over cannot be excluded. It is also possible that unblinding
of patients may have occurred due to the recognition of FPNS-
related adverse events, which were more common after episodes
were treated with FPNS than placebo.
Fentanyl has been demonstrated to be efficacious and well tol-
erated in the treatment of BTCP when administered transmucosal-
ly. In pursuit of an optimal delivery method, strenuous efforts are
going on to develop new formulations for the pharmaceutical mar-
ket. Preliminary evidence suggests that intranasal formulations of
fentanyl may be advantageous over other transmucosal routes, in
terms of rapid onset of action [8], but more research is needed.
The well-designed and conducted study by Portenoy et al. [10]
shows that FPNS is efficacious in comparison to placebo and well
tolerated in BTCP. However, current requirements for the market
authorization of drugs and the practice of evidence-based medi-
cine necessitates that all new pharmaceutical formulations that
significantly differ from conventional formulation must be studied
in significantly large and randomized controlled studies. Transmu-
cosal formulations of fentanyl, such as FPNS, will undoubtedly ben-
efit patients suffering from BTCP when incorporated into routine
 Ò
566 Commentary / PAIN 151 (2010) 565–566
clinical practice. The mainstay of BTCP treatment, however, still
rests on adequate management of background pain, with long-
term opioids and other methods.
Conflict of interest
Dr. Nora M Hagelberg has no conflicts of interest. Dr. Klaus T
Olkkola has worked as a pharmacokinetic consultant for Akela
Pharma Inc., Turku, Finland.
[10] Portenoy R, Burton AW, Gabrail N, Taylor D, on behalf of the fentanyl Pectin
References
[1] Coluzzi PH, Schwartzberg L, Conroy JD, Charapata S, Gay M, Busch MA, Chavez
[11] Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and
J, Ashley J, Lebo D, McCracken M, Portenoy RK. Breakthrough cancer pain: a
randomized trial comparing oral transmucosal fentanyl citrate (OTFCÒ) and
[12] Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebo-
morphine sulphate immediate release (MSIRÒ). Pain 2001;91:123–30.
[2] Christrup LL, Foster D, Popper LD, Troen T, Upton R. Pharmacokinetics, efficacy,
and tolerability od fentanyl following intranasal versus intravenous
administration in adults undergoing third-molar extraction: A randomized,
double-blind, double-dummy, two-way, cross-over study. Clin Ther
2008;30:469–81.
[3] Farrar JT, Cleary J, Rauck R, Busch M, Nordbrock E. Oral transmucosal fentanyl
citrate (OTFC): Randomized, double-blinded, placebo-controlled trial for
treatment of breakthrough pain in cancer patients. J Natl Cancer Inst
1998;90:611–6.
[4] Farr SJ, Otulana BA. Pulmonary delivery of opioids as pain therapeutics. Adv
Drug Deliv Rev 2006;58:1076–88.
[5] Jekunen AP, Cotterill-Jones C, Dewlan P, Tanner T, Sikorska H, Asking L,
Jouhikainen T. Dose linearity of inhaled fentanyl with comparative
pharmacokinetics to transmucosal fentanyl. J Clin Oncol (2006 ASCO Annual
Meeting Proceedings Part I) 2006;24:8629.
[6] Katz N. Enriched enrollment randomized withdrawal trial designs of
analgesics. Focus on methodology. Clin J Pain 2009;25:797–807.
[7] Kress HG, Orońska A, Kaczmarek Z, Kaasa S, Colberg T, Nolte T. Efficacy and
tolerability of intranasal fentanyl spray 50 to 200lg for breakthrough pain in
patients with cancer: A phase III, multinational, randomized, double-blind,
placebo-controlled, crossover trial with 10-month, open-label extension
treatment period. Clin Ther 2009;31:1177–91.
[8] Mercadante S, Radbruch L, Davies A, Poulain P, Sitte T, Perkins P, Colberg T,
Camba MA. A comparison of intranasal fentanyl spray with oral transmucosal
fentanyl citrate for the treatment of breakthrough cancer pain: and open-label,
randomised, crossover trial. Curr Med Opin Res 2009;25:2805–15.
[9] Moksnes K, Fredheim OM, Klepstad P, Kaasa S, Angelsen A, Nilsen T, Dale O.
Early pharmacokinetics of nasal fentanyl: is there a significant arterio-venous
difference? Eur J Clin Pharmacol 2008;64:497–502.
Nasal Spray 043 group. A multicenter, placebo-controlled, double-blind,
multiple-crossover study of fentanyl pectin nasal spray (FPNS) in the
treatment of breakthrough cancer pain. Pain 2010;151:617–24.
impact in patients with cancer pain. Pain 1999;81:129–34.
controlled study of fentanyl buccal tablet for breakthrough pain in opioid-
treated patients with cancer. Clin J Pain 2006;22:805–11.
⇑
Nora M. Hagelberg
Klaus T. Olkkola
Department of Anaesthesiology, Intensive Care,
Emergency Care and Pain Medicine,
University of Turku and Turku University Hospital,
P.O. Box 52, FI-20521 Turku, Finland
⇑ Tel.: +358 2313 2960.
E-mail address: nora.hagelberg@tyks.fi (N.M. Hagelberg).
Received 18 August 2010
Accepted 18 August 2010