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No. of Pages 6
ARTICLE IN PRESS
Critical Reviews in Oncology/Hematology xxx (2011) xxx–xxx
The use of rapid onset opioids for breakthrough cancer pain:
The challenge of its dosing
Sebastiano Mercadante a,b,∗
a
Anesthesia and Intensive Care Unit and Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Palermo, Italy
b Department of Anesthesia, Intensive Care & Emergencies, University of Palermo, Italy
Accepted 10 December 2010
Contents
1.
2.
3.
4.
5.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Oral opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Parenteral opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ROOs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Oral transmucosal fentanyl citrate (OTFC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Fentayl buccal tablets (FBT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Intranasal Nasal fentanyl (INFS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. Sublingual fentanyl (SLF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The problem of dosing ROOs for the treatment of BTcP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
Breakthrough cancer pain (BTcP) has been defined as a transitory increase in pain intensity on a baseline pain of moderate intensity in
patients on analgesic treatment regularly administered. This review provides updated information about the use of opioids for the treatment
of BTcP, with special emphasis on the use of new rapid onset opioids (ROOs).
Due to its slow onset to effect oral opioids cannot be considered an efficacious treatment for BTcP. Parenteral opioids may provide rapid
onset of analgesia, but not always available particularly at home. Different technologies have been developed to provide fast pain relief
with potent opioid drugs such fentanyl, delivered by non-invasive routes. Transmucosal administration of lipophilic substances has gained a
growing popularity in the last years, due to the rapid effect clinically observable 10–15 min after drug administration, obtainable in non-invasive
forms. Fentanyl is a potent and strongly lipophilic drug, which matches the characteristics to favour the passage through the mucosa and then
across the blood–brain barrier to provide fast analgesia. Transmucosal, buccal, sublingual, and intranasal fentanyl showed their efficacy in
comparison with oral morphine or placebo and are available for clinical use in most countries. All the studies performed with ROOs have
recommended that these drugs should be administered to opioid-tolerant patients receiving doses of oral morphine equivalents of at least
60 mg. The choice of the dose of ROO to be prescribed as needed remains controversial. The need of titrating opioid doses for BTcP has been
commonly recommended in all the controlled studies, but has never been substantiated in appropriate studies.
© 2010 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cancer pain; Breakthrough pain; Fentanyl; Opioids
∗ Corresponding author at: Anesthesia and Intensive Care Unit & Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Via san Lorenzo 312,
90145 Palermo, Italy. Tel.: +39 091 6806521; fax: +39 091 6806110.
E-mail addresses: [email protected], [email protected].
1040-8428/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.critrevonc.2010.12.002
Please cite this article in press as: Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: The challenge of its dosing.
Crit Rev Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2010.12.002
ONCH-1497;
No. of Pages 6
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1. Introduction
Patients with cancer pain often present with fluctuations
in pain intensity. Breakthrough cancer pain (BTcP) has been
defined as a transitory increase in pain intensity on a baseline
pain of moderate intensity in patients on analgesic treatment regularly administered [1]. Patients are often receiving
basal medication for their pain which is otherwise considered
acceptable. Although highly variable, BTcP is typically rapid
in onset, moderate to severe in intensity, and relatively short
in duration [2]. Three principal categories of BTcP have been
identified: (a) spontaneous pain with no evident precipitating
event; (b) incident pain, with an evident precipitating cause
or event, for example due to activity; (c) end of dose failure,
associated with therapeutic holes due to a reduction in blood
analgesic levels of medications provided at regular intervals.
The latter group does not exactly corresponds to the definition of BTcP, expressing a status of inappropriate analgesia,
although from a clinical perspective it still represents a clinical problem to be addressed as BTcP. Another way to classify
BTcP could be based on the presence of volitional or precipitant factors, which have been identified in more than 50% of
patients. Therefore, for each category different subtypes can
be also identified.
Previous surveys have found that this phenomenon, is
highly prevalent among patients with cancer pain and predicts more severe pain, pain-related distress and functional
impairment, and relatively poor quality of life [2]. In different surveys 50–90% of cancer patients with pain have
been reported to experience intermittent flares of their pain,
although using different definitions and methodology [1–5].
These figures have been confirmed in a large international survey assessing the prevalence of BTcP, showing a prevalence
of about 65% [6].
Pharmacological treatment regimes are based on implementation of primary therapies, optimization of scheduled
analgesia [7], and specific treatment of BTcP [2,3]. The aim
of this review is to provide updated information about the use
of opioids for the treatment of BTcP, with special emphasis
on the use of new rapid onset opioids (ROOs).
2. Oral opioids
The availability of supplemental doses of oral opioids in
addition to the continuous analgesic medication is the main
treatment suggested to manage pain flares. Current dosing
recommendations for BTcP generally suggest that the effective dose of BTcP medication must be a percentage of a
patient’s total daily opioid dose [8]. These recommendations,
which are based entirely on anecdotal experience, favour the
selection of an oral short-acting opioid at a dose proportionate to the total daily dose. However, an oral dose form
can take a longer time to relieve pain, with peak concentrations achieved within 30–45 min. Hydromorphone, and
oxycodone, all undergo extentive first pass effect, and are
hydrophyilic in nature, showing a late onset of analgesia of
30–60 min. Although the use of the same opioid to treat BTcP
as to treat baseline pain is common place, it has been shown
that the peak effect of orally administered opioids is about
60 min [9]. Due to its slow onset to effect oral opioids cannot be considered an efficacious treatment for BTcP. In a
study of 50 oncology patients, equal numbers of individuals
used morphine, oxycodone, hydromorphone, methadone or
oral transmucosal fentanyl the average time to meaningful
pain relief following their administration was about 30 min,
whereas the average duration of BTcP was 35 min (range
15–60).
Non-adherence with oral opioids, including morphine,
may not be surprising. The temporal characteristics of most
BTcP events suggest the use of drugs with a faster onset of
action [10]. Thus, more recent recommendations have underlined that orally administered opioids are unsuitable for pains
with a short onset and duration [11,12]. Rather, they appear
effective when given timely before pain occurs or in well characterized BTcP events with a gradual onset [13]. For example,
the slow analgesic peaks achieved with oral opioids could be
useful when administered 15–30 min before starting physical
activity in patients with predictable incident pain, or during
opioid titration phase.
Effervescent morphine resulted in faster relief of BTcP
compared to immediate release morphine. The solution
rapidly passes through the stomach and could result in a faster
transit into the small intestine where the active ingredient is
absorbed [14].
3. Parenteral opioids
As pain relief is usually required urgently, routes of administration designed to delivery drugs rapidly are often chosen.
A shorter onset of effect is commonly obtainable only with
parenteral administration of opioid analgesics. Intravenous
morphine (IV-MO) has been found to be highly effective and
safe, as only a low intensity of opioid-induced adverse effects
was observed, even when administering large doses [15]. A
recent confirmatory study of a large sample of patients confirmed that IV-MO administered for the management of BTcP
in doses proportional to the basal opioid regimen, even given
in older patients or relatively large doses, did not result in lifethreatening adverse effects while being effective by patients
in most cases [16]. While IV-MO is feasible in acute units,
in most other centres is not favourite, and at home injections
are not easily manageable. Subcutaneous route is commonly
preferred in an hospice setting, although the onset of action
may be not fast enough. Hydromorphone has been delivered
subcutaneously using a “pain pen” [17].
4. ROOs
Different technologies have been developed to provide fast
pain relief with potent opioid drugs such fentanyl, deliv-
Please cite this article in press as: Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: The challenge of its dosing.
Crit Rev Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2010.12.002
ONCH-1497;
ARTICLE IN PRESS
No. of Pages 6
S. Mercadante / Critical Reviews in Oncology/Hematology xxx (2011) xxx–xxx
ered by non-invasive routes. Transmucosal administration
of lipophilic substances has gained a growing popularity in
the last years, due to the rapid effect clinically observable
10–15 min after drug administration, obtainable in noninvasive forms. Not all drugs are suitable for transmucosal
administration. Fentanyl is a potent and strongly lipophilic
drug, which matches the characteristics to favour the passage
through the mucosa and then across the blood–brain barrier to
provide fast analgesia. All the studies performed with ROOs
have recommended that these drugs should be administered
to opioid-tolerant patients receiving doses of oral morphine
equivalents of at least 60 mg.
4.1. Oral transmucosal fentanyl citrate (OTFC)
OTFC is a fentanyl-impregnated lozenge, available in six
dosage strengths (200, 400, 600, 800, 1200, and 1600 ␮g).
The oral mucosal route of delivery offers several advantages.
The oral mucosa is highly permeable and is highly vascularized, and has a large surface area and a relatively uniform
temperature. The lozenge is gently rubbed against the buccal
mucosa until it has completely dissolved (which should take
no longer than 15 min, if appropriately used). An active participation is required to correctly use the lozenge. Fentanyl is
absorbed in about 15 min through the oral mucosa. Absorption rate and total bioavailability for fentanyl was greater and
occurred sooner after OTFC administration than after oral
administration. Serum fentanyl levels achieved with OTFC
are proportional to the dose administered [18]. Mucositis, and
local infection, and dry mouth may limit the use or reduce the
absorption of the drug. Absolute availability is about 50%.
However, the percentage absorbed by mouth and immediately
available for treating BTcP is about 25% [18].
Several trials have shown that OTFC in doses ranging
from 200 ␮g to 1600 ␮g is an effective analgesic for BTcP
in patients already receiving maintenance opioid therapy for
chronic cancer pain. This approach produces a faster onset of
relief and a greater degree of pain relief than the placebo
or oral morphine, at 15, 30, and 60 min [9,19–21]. The
adverse effects associated with OTFC in studies of patients
with chronic cancer pain were typical opioid side effects.
Some of the adverse effects may have been attributable to
patients’ underlying disease or to other analgesics or medications patients were using at the time of the study, other than
opioids used for background analgesia [18]. A lack of relationship between the effective OTFC dose and fixed schedule
opioid regimen, regardless of the opioid used, was observed
suggesting the need to titrate the dose of OTFC.
4.2. Fentayl buccal tablets (FBT)
FBT is a formulation of transmucosal fentanyl designed
to provide a rapid penetration of fentanyl through the buccal mucosa by using effervescence to cause PH shifts that
enhance the rate and extent of fentanyl absorption. A reasonable level of salivation is needed to allow dissolution. The
3
tablet is placed between the upper gum and cheek, above a
rear molar tooth, and patients are instructed to gently rub outside of the cheek until all material is dissolved. Fentanyl is
rapidly absorbed from FBT with a mean peak plasma concentration reached in 35–90 min. The absolute bioavailability
of fentanyl from FBT was greater that from OTFC. FBT
is absorbed in approximately equal proportions through the
buccal mucosa and the gastrointestinal tract whereas, with
OTFC, the proportion absorbed through the buccal mucosa
was lower (22%) than that absorbed gastrointestinally (78%)
[22]. Thus the drug immediately available to treat BTcP
is about the double of OTFC (48% versus 22%) [23,24].
Sublingual placement of FBT resulted in similar values of
pharmacokinetic parameters [25]. Patients with cancer, particularly those undergoing chemotherapy or radiotherapy,
may develop oral mucositis. In patients with mild mucositis
the absorption of fentanyl with FBT was not different from
that of patients without mucositis [26].
Controlled studies have reported the efficacy and safety of
FBT in opioid-tolerant cancer patients with BTcP even after
10 min, after performing a titration phase to determine the
effective dose. There seemed to be no relationship between
effective FBT dose and the dose of baseline opioid regimen
[27,28].
4.3. Intranasal Nasal fentanyl (INFS)
The intranasal administration route is an alternative with
several benefits, including fast systemic penetration and the
potential for self administration, as well as being acceptable to patients with reduced salivary flow. INFS has been
associated with minimal local irritation in the nasal cavity.
In a pharmacokinetic study in cancer patients, fentanyl was
quickly absorbed through the nasal mucosa, attaining peak
plasma concentrations within 12–15 min for all the dosage
strengths examined (50–200 ␮g) [29]. After a titration phase
to determine the effective dose, the use of INFS at doses
of 50–200 ␮g was associated with an onset of activity at
10 min and a more effective treatment of BTcP compared
with placebo [30]. The only existing study comparing two
different ROOs showed a decrease in pain intensity which
was significantly greater with INFS than OTFC from 5 min
post dosing. More patients attained significantly faster meaningful pain relief with INFS than OTFC, and more patients
preferred INFS to OTFC [31].
4.4. Sublingual fentanyl (SLF)
The sublingual mucosa is well suited for the delivery of
ROO. The high vasculariry and good permeability of the sublingual mucosa offer the potential for a rapid absorption of
lipophilic opioids such as fentanyl [32]. In addition, this is a
convenient and popular method for patients to self-administer
effective pain relief medication that matches the temporal
characteristics of BTcP. A novel rapidly absorbed sublingual
form following the administration of single doses of 100,
Please cite this article in press as: Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: The challenge of its dosing.
Crit Rev Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2010.12.002
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200, and 400 ␮g provided plasma concentration increasing
linearly with dosage [33].
Two studies assessed the clinical efficacy of SLF. In a
clinical study, SLF was administered in opioid-tolerant cancer patients. Placebo, and doses of 100, 200, and 400 ␮g
were administered in random order at four pain episodes.
Pain intensity significantly decreased with SLF 400 in comparison with placebo at 15 min, while doses of 100 and
200 showed only a trend towards improved pain relief. The
incidence or severity of adverse effects did not increase
with increasing SLF dose [34]. In a placebo-controlled conducted in opioid-tolerant cancer patients, SLF, administered
for BTcP, provided significant improvements in pain intensity compared to placebo, from 10 min post-administration
and throughout the 60 min post-dose assessment period
[35].
5. The problem of dosing ROOs for the treatment of
BTcP
The choice of the dose of ROO to be prescribed as needed
remains controversial. The need of titrating opioid doses for
BTcP has been commonly recommended in all the controlled
studies with OTFC and FBT. The reasons for these findings
are not clearly explained, considering that the presence of
tolerance should suggest a dose proportional to those used
for background analgesia. An expected tolerance to adverse
effects in patients chronically exposed to opioids has been
found, despite serum fentanyl levels as high as 6–8 ng/mL
[18]. Dose titration may make the practical use of ROOs
difficult in the daily activity, particularly at home or in outpatients. Moreover, using different pieces or spray of ROOs
for treating each episode may be time consuming exceeding
the spontaneous duration for BTcP which can spontaneously
subside, as evidenced by successful placebo-treated patients.
Most patients may be reluctant to try the dose and avoid to
use these drugs, preferring, at the end, traditional oral dosing
of morphine [13].
More information is necessary. For instance, OTFC, given
in doses proportional to the basal opioid regimen, has been
found quite effective and, above all, safe, avoiding to titrate
the dose, which is considered boring for patients, reducing
their compliance with the treatment, suggesting that opioids
given as needed could be safety used at proportional doses,
regardless of the modality of administration. Preliminary and
confirmatory surveys have shown the safety of this approach
in a large number of patients with no life-threatening adverse
effects occurring even in older patients [16,36]. Respiratory
depression, which is the most feared adverse effect, has never
occurred, and no emergency call was needed [37]. Finally, in
a recent survey reproducing a real clinical scenario, patients
receiving a mean oral morphine dose of 132 mg, required
800 ␮g of OTFC after dose titration [10], suggesting that
titration process may provide even higher doses that those
expected by using proportional doses to basal opioid regimen.
These observations contrast with almost all studies of
OTFC. Some data need accurate interpretation. For example,
in successful patients the regular rescue dose was a moderate
predictor of the effective OTFC dose. In one of the controlled
studies of OTFC, a relationship between the OTFC dose and
the fixed scheduled opioid had been already found, and regular rescue dose was a moderate predictor of the effective
OTFC dose. However, 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
[20]. Finally, recent 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 [38]. The need to titrate has never been
determined on the basis of a real comparison between titration
strategy and no titration strategy [39].
It is likely that patients receiving high doses of opioids as
basal analgesic regimen will not be candidates for titration
with minimal initial doses of ROOs, as they are opioidtolerant, and the process would be time consuming. Thus, a
reliable compromise between the different opinions could be
to start with relatively higher doses of ROO in highly-tolerant
patients, until more information will be available to settle
the question. Future studies should settle this controversial
issue.
Conflict of interest statement
The author received grants for consultation or lectures
from Nycomed, Archimedes, Abstral, Dompè, Cephalon,
Mundipharma, Pfizer, QX Pharma, Janssen, Grunenthal,
Wyeth.
Reviewers
Josep Porta Sales, M.D., Head of the Palliative Care
Service, Catalonian Institute of Oncology, Hospitalet de Llobregat, Av. Gran Via s/n, Km 2,7, E-08907 Barcelona, Spain.
Zbigniew Zylicz, M.D., Consultant in Palliative Medicine,
Dove House Hospice, Hull, HU8 8DH, United kingdom.
Michaela Berkovitch, M.D., Chair, Israel Palliative Medical Society, The Chaim Sheba Medical Center, Oncological
Hospice, Tel Hashomer, 52621, Israel.
Franco De Conno, M.D., Istituto Nazionale dei Tumori,
Rehabilitation and Palliative Care, Via Venezian 1, I-20133
Milan, Italy.
References
[1] Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence
and characteristics. Pain 1990;41:273–81.
[2] Portenoy RK, Payne D, Jacobson P. Breakthrough pain: characteristics
and impact in patients with cancer pain. Pain 1999;81:129–34.
Please cite this article in press as: Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: The challenge of its dosing.
Crit Rev Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2010.12.002
ONCH-1497;
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ARTICLE IN PRESS
S. Mercadante / Critical Reviews in Oncology/Hematology xxx (2011) xxx–xxx
[3] Mercadante S, Arcuri E. Breakthrough pain in cancer patients: pathophysiology and treatment. Cancer Treat Rev 1998;24:425–32.
[4] Mercadante S, Radbruch L, Caraceni A, et al. Episodic (breakthrough)
pain. Cancer 2002;94:832–9.
[5] Haugen DF, Hjermstad MJ, Hagen N, Caraceni A, Kaasa S. European
Palliative Care Research Collaborative (EPCRC) assessment and classification of cancer breakthrough pain: a systematic literature review.
Pain 2010;149:476–82.
[6] Caraceni A, Martini C, Zecca E, et al. Working group of an IASP
task force on cancer pain breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliat
Med 2004;18:177–83.
[7] Mercadante S, Villari P, Ferrera P, Casuccio A. Optimization of opioid
therapy for preventing pain associated with bone metastases. J Pain
Symptom Manage 2004;28:505–10.
[8] Hanks GW, Conno F, Cherny N, et al. Expert Working group of the
Research Network of the European Association for Palliative Care
Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001;84:587–93.
[9] Coluzzi PH, Schwartzberg L, Conroy JD, et al. Breakthrough cancer
pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulphate immediate release (MSIR). Pain
2001;91:123–30.
[10] Zeppetella GB. Opioids for cancer breakthrough pain: a pilot study
reporting patient assessment of time to meaningful pain relief. J Pain
Symptom Manage 2008;35:563–7.
[11] Bennett D, Burton AW, Fishman S, et al. Consensus panel recommendations for the assessment and management of breakthrough pain. Part
2. Management. Pharm Ther 2005;30:354–61.
[12] Davies AD, Dickman A, reid C, Stevens A, Zeppetella G. The management of cancer-related breakthrough pain: recommendations of
a task group of the science committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur J Pain 2009;13:
331–8.
[13] Davies A, Vriens J, Kennett A, McTeggart. An observational study of
oncology patients’ utilization of breakthrough pain medication. J Pain
Symptom Manage 2008;35:406–11.
[14] Freye E, Levy JV, Braun D. Effervescent morphine results in faster
relief of breakthrough pain in cancer patients compared to immediate
release morphine tablet. Pain Pract 2007;7:324–32.
[15] Mercadante S, Villari P, Ferrera P, Bianchi M, Casuccio A. Safety and
effectiveness of intravenous morphine for episodic-breakthrough pain,
using a fixed ratio with the oral daily morphine dose. J Pain Symptom
Manage 2004;27:352–9.
[16] Mercadante S, Intravaia G, Villari P, Ferrera P, Riina S, Mangione
S. Intravenous morphine for episodic-breakthrough pain in an acute
palliative care unit: a confirmatory study. J Pain Symptom Manage
2008;35:307–13.
[17] Enting RH, Mucchiano C, Oldenmenger WH, et al. The “pain pen”
for breakthrough cancer pain: a promising treatment. J Pain Symptom
Manage 2005;29:213–7.
[18] Aronoff G, Brennan M, Pritchard D, Ginsberg B. Evidence-based oral
transmucosal fentanyl citrate (OTFC) dosing guidelines. Pain Med
2005;6:305–14.
[19] Portenoy RK, Payne R, Coluzzi P, et al. Oral transmucosal fentanyl
citrate (OTFC) for the treatment of breakthrough pain in cancer patients:
a controlled dose titration study. Pain 1999;79:303–12.
[20] Christie J, Simmonds M, Patt R, et al. Dose-titration multicenter study
of transmucosal fentanyl citrate for the treatment of breakthrough pain
in cancer patients using transdermal fentanyl for persistent pain. J Clin
Oncol 1998;16:3238–45.
[21] 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:
611–6.
[22] Blick S, Wagstaff AJ. Fentanyl buccal tablets in breakthrough pain in
opiooid-tolerant patients with cancer. Drugs 2006;66:2387–93.
5
[23] Darwish M, Tempero K, Kirby M, Thompson J. Pharmacokinetics and
dose proportionality of fentanyl effervescent buccal tablets in healthy
volunteers. Clin Pharmacokinet 2005;44:1279–86.
[24] Darwish M, Kirby M, Robertson P, Tracewell W, Jiang JG. Absorption
of fentanyl from fentanyl buccal tablet in cancer patients without oral
mucositis: a pilot study. Clin Drug Invest 2007;27:605–11.
[25] Darwish M, Kirby M, Jiang JG, Tracewell W, Robertson P. Bioequivalence following buccal tablet 400 microg in healthy subjects. Clin Drug
Invest 2008;28:1–7.
[26] Darwish M, Kirby M, Robertson P, Tracewell W, Jiang JG. Absolute and
relative bioavailability of fentanyl buccal tablet and oral transmucosal
fentanyl citrate. J Clin Pharmacol 2007;47:343–50.
[27] Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebocontrolled study of fentanyl buccal tablet for breakthrough pain in
opioid-treated patients with cancer. Clin J Pain 2006;22:805–11.
[28] Slatkin NE, Xie F, Messina J, Segal TJ. Fentanyl buccal tablet for relief
of breakthrough pain in opioid-tolerant patients with cancer-related
chronic pain. J Support Oncol 2007;5:327–34.
[29] Kaasa S, Moksnes K, Nolte T, Lefebvre-Kuntz D, Popper L, Kress HG.
Pharmacokinetics of intranasal fentanyl spray in patients with cancer
and breakthrough pain. J Opioid Manage 2010;6:17–26.
[30] Kress HG, oronska A, Kaczmarek Z, et al. Efficacy and tolerability
of intranasal fentanyl spray 50 to 200 ␮g for breakthrough pain in
patients with cancer: a phase III, multinational, randomized, doubleblind, placebo-controlled, crossover trial with a 10 month, open-label
extension treatment period. Clin Ther 2009;31:1177–91.
[31] Mercadante S, Radbruck L, Davies A, et al. A comparison of intranasal
fentanyl spray with oral transmucosal fentanyl citrate for the treatment
of breakthrough cancer pain: an open-label, randomized, crossover trial.
Curr Med Res Opin 2009;25:2805–15.
[32] Bredenberg S, Duberg M, Lennernas B, et al. In vitro and in vivo
evaluation of a new sublingual tablet system for rapid oromucosal
absorption using fentanyl citrate as the active substance. Eur J Pharm
Sci 2003;20:327–34.
[33] Lennernas B, Hedner T, Holmberg M, Nystrom C, Lennernas H.
Pharmacokinetics and tolerability of different doses of fentanyl sublingual administration of a rapidly dissolving tablet to cancer patients:
a new approach to treatment of incident pain. Br J Clin Pharm
2004;59:249–53.
[34] Lennernäs B, Frank-Lissbrant I, Lennernäs H, Kälkner KM, Derrick R,
Howell J. Sublingual administration of fentanyl to cancer patients is an
effective treatment for breakthrough pain; results from a randomized
phase II study. Palliat Med 2010;24:286–93.
[35] Rauck RL, 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;25:2877–85.
[36] Mercadante S, Villari P, Ferrera P, Casuccio A, Mangione S, Intravaia G.
Transmucosal fentanyl vs intravenous morphine in doses proportional
to basal opioid regimen for episodic-breakthrough pain. Br J Cancer
2007;96:1828–33.
[37] Mercadante S, Villari P, Ferrera P, Mangione S, Casuccio A. The use
of opioids for breakthrough pain in acute palliative care unit by using
doses proportional to opioid basal regimen. Clin J Pain 2010;26:306–9.
[38] Hagen NA, Fisher K, Victorino C, Farrar JT. A titration strategy is
needed to manage breakthrough cancer pain effectively: observations
from data pooled from three clinical trials. J Palliat Med 2007;10:47–55.
[39] Mercadante S. Breakthrough pain: on the road again. Eur J Pain
2009;13:329–430.
Biography
Sebastiano Mercadante, M.D. is Director of the Anesthesia and Intensive Care unit and Pain relief and palliative
care unit at La Maddalena Cancer Center, Palermo, Italy.
Please cite this article in press as: Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: The challenge of its dosing.
Crit Rev Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2010.12.002
ONCH-1497;
6
No. of Pages 6
ARTICLE IN PRESS
S. Mercadante / Critical Reviews in Oncology/Hematology xxx (2011) xxx–xxx
He is Professor of palliative Medicine at the University of
Palermo. He has authored over 350 scientific publications
and edited, or wrote chapters, forty-two books. Associated
Editor, editorial Board and/or referee of more than 30 international peer-reviewed journals in the field of pain and symptom
management, and anesthesiology He was a board member of
dozens of scientific committees of international congresses
Winner of award of excellence in scientific research, American Academy of Hospice and palliative medicine, Boston
2010.
Please cite this article in press as: Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: The challenge of its dosing.
Crit Rev Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2010.12.002