Breakthrough pain: Focus on Fentanyl Buccal Tablet

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Breakthrough pain: Focus on Fentanyl Buccal Tablet
Remigiusz Lecybyl1 and Magdi Hanna2
1Lewisham University Hospital, London, UK. 2Analgesia and Pain Research Hub, Beckeham, UK. email: cambodja@amp.edu.pl
Abstract: Breakthrough pain (BTP) management is an unmet clinical need. BTP is poorly diagnosed, rarely evaluated and inadequately
treated. BTP is transitory exacerbation of pain experienced by the patient who has relatively stable and adequately controlled baseline pain.
BTP is reported to be common in adults and children with cancer as well as in non-cancer diseases associated with acute/chronic pain.
Successful management of breakthrough pain depends on adequate assessment, appropriate treatment (cause of pain and symptomatic) and
adequate reassessment. Ideal medication for BTP should be characterized with good efficacy and minimal side effects. Pharmacodynamic
profile should mimic dynamics of BTP. Strong, short acting analgesics (e.g. opioids) administrated by route which allow quick action
had potential to fulfil criteria for ideal ‘rescue’ medication for BTP. Fentanyl Buccal tablets (FBT; Fentora®, Frazer, PA, Cephalon Inc.)
is novel delivery system for fentanyl citrate. FBT utilize OraVescent (r) technology to improve bioavability and speed of transmucosal
delivery. Alternate routes of administration could further improve efficacy of BTP management. Intranasal and intrapulmonary routes are
under exploration. Recently introduced new delivery systems for opioids medication do represent an improvements in BTP management,
however BTP is still a major challenge to pain and palliative physicians.
Keywords: cancer pain, breakthrough pain, opioids, analgesia, fentanyl buccal tablets
Clinical Medicine Insights: Therapeutics 2010:2 89–98
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Lecybyl and Hanna
Introduction
are classified as having transitory pain16 and patients
Breakthrough pain (BTP) remains on of the most
with poorly controlled background pain with or with-
challenging clinical problems for physicians and
out severe transitory episodic exacerbations of pain are
patients alike. Itt is poorly diagnosed, rarely evaluated
classified as having uncontrolled pain.16
and inadequately treated.1 BTP is reported to be com-
mon in adults and children with cancer2–6 as well as in
Prevalence of BTP
non-cancer syndromes associated with acute/chronic
In a recent international survey, clinicians reported BTP
pain.7,8 Currently there is growing interest in BTP
in 23%–90% of adult cancer patients,3–6,11,16–19 and 74%
management generated by a greater awareness of the
in opioids treated non-cancer pain patients.8 BTP appears
problem of breakthrough pain (secondary to improve-
to be more common in patients with advance disease.20
ment in the management of background pain) as well
In majority of studies the prevalence of incident related
as its significant negative impact on quality of life,
BTP (range 43%–64%) was higher than the prevalence of
and fuelled by an increasing range of pharmacologi-
spontaneous BTP (relevance range: 17%–38%).4,10,11,16,19
cal options for the treatment of breakthrough pain.9
Only one study observed opposite prevalence (sponta-
BTP has a significant negative impact on quality of
neous 59%, incident 24%).6 Prevalence of BTP varies
life.10,11 Complications of BTP are summarized in
between different groups of patients21 and is affected by
Table 1.3,5,10–12
certain language/geographical variables.17,22 BTP is a
poor prognostic indicator.23
Definition of BTP
BTP is a transitory exacerbation of pain experienced
Assessment of BTP
by a patient who has relatively stable and adequately
Breakthrough pain is not a single entity, but a spectrum
controlled baseline pain.13 Bennett proposed a similar
of very different entities. The clinical features vary from
definition: BTP is an abrupt, short lived and intense
individual to individual, and may vary within individu-
pain that ‘breaks through’ the around the clock anal-
als over time.24 Table 4 summarizes diagnostic criteria
gesia that controls persistent pain.14 Other names
for BTP.16 Successful management of breakthrough
include: episodic pain, exacerbation of pain, pain
pain depends on adequate assessment25 (Table 5),
flare, transient pain, transitory pain.9 The Expert
appropriate treatment (cause of pain and symptomatic)
Working Group of the European Association for
and adequate reassessment.26 Many patients have more
Palliative Care (EAPC) has suggested that the term
than one type of breakthrough pain10,16 and an associa-
‘breakthrough pain’ should be replaced by the terms
tion between the presence of breakthrough pain and the
‘episodic pain’ or ‘transient pain’.15 Common clinical
intensity/frequency of the background pain has been
features of BTP are summarized in Table 2.10
reported.10,17 Circadian variation in the occurrence of
BTP has been reported (86% patients experienced BTP
Classification of BTP
during day and only 45% during night).4 Formal assess-
Classification of BTP is presented in Table 3 (modified
ment tools for BTP are presented in Table 6.12,16,27
from12). End-of dose failure is not a subtype of break-
through pain it should rather be simply classified as
Treatments of BTP
inadequately controlled pain.12 Patients with no back-
Holistic/multimodal approachs for BTP treatment
ground pain but who have severe episodic bouts of pain
have been proposed. Principles of BTP management24
Table 1. Breakthrough pain could lead to following complications.
•  Physical (decreased functioning)—predominantly due to mobilizing difficulty and sleep disturbances
•  Psychological—predominantly mood disturbances, anxiety and depression
•  Social—predominantly due to movement related pain
•   economical—BTP is associated with increased use of health care services (e.g. longer stays in hospital) which lead to an
increase in costs for the health service, patient and their corers
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Breakthrough pain
Table 2. Common clinical features of breakthrough pain.
Table 4. Diagnostic criteria for breakthrough pain.
•  Frequent in occurrence
•   The presence of stable analgesia in the previous
•  Acute in onset
48 hours
•  Short in duration
•   The presence of controlled background pain in the
previous 24 hours
•  Moderate to severe in intensity
•   The presence of temporary flares of severe or
•  Related to background pain
excruciating pain in the previous 24 hours
are presented in Table 7. Physical, pharmacological,
with taking any dose of opioids (e.g. somnolence,
neuro-modulatory treatments and invasive procedures
nausea, vomiting, and dizziness);37 one can infer that
are used in BTP management4,12,15,18,21,24,28–33 (Table 8).
significant increse in the intensity of side effects from
Pharmacological management should be tailored to
BTP medications should be less likely to occur when
the type of breakthrough pain34–36 (Table 9).
BTP medication is administered to an opioid tolerant
patient. This concept led to the use of these potent
Ideal ‘Rescue’ Medication for BTP
ROOs only in opioid tolerant patients. While only
The ideal medication for BTP should be character-
approved for use in cancer pain, the utility of ROOs
ized by good efficacy and minimal side effects. The
for pain in opioid tolerant non-cancer pain patients
pharmacodynamic profile should mimic the dynamics
has been reported.38–40
of BTP (Table 10). A potent, short acting analgesic
Traditionally it has been suggested that one should
(e.g. opioid) administrated by a route which allows for
use the same opioid to treat background and break-
a rapid onset of action has the potential to fulfil the cri-
through pain.41 The current approach utilizes opioids
teria for an ideal ‘rescue’ medication for BTP. A new
according to their pharmacodynamic properties and
class of opioids, Rapid Onset Opioids (ROOs), has
their pharmakokinetics: long acting for background
been developed in an attempt to address the “unmet
pain and short acting (and preferably rapid onset) for
need” of breakthrough pain management.
breakthrough pain. Sometimes the same opioid is used
Patients on chronic intake of opioids would have
for background and BTP as when a fentanyl patch is
developed some tolerance to opioid side effects.
used to treat background pain and a rapid onset buc-
Since the side effects associated with taking a break-
cal or nasal fentanyl (transmucosal) preparation is
through dose of opioid are similar to those associated
Table 5. Assessment of pain.
Table 3. Classification of breakthrough pain.
•  Onset of pain
• Spontaneous pain (idiopathic pain)—pain occurs
•  Temporal pattern of pain
unexpectedly
•  Site of pain
• Incident pain (precipitated pain)—pain related to
specific event*
•  Radiation of pain
• volitional incident pain—precipitated by voluntary
•  Quality of pain
act (e.g. walking)
•  Intensity of pain
• Non-volitional incident—pain precipitated by
•  exacerbating factors
involuntary act (e.g. coughing)
•  Relieving factors
• Procedural pain—related to a therapeutical
•  Response to analgesics
interventions (e.g. wound dressing)
•  Response to other interventions
• End of dose failure—due to insufficient overall dose of
opioids**
•  Associated physical symptoms
* Incident pain related to movement (volitional or non-volitional) is called
•  Associated psychological symptoms
movement related pain.
•  Interference with daily activities
**Often not regarded as true breakthrough pain.
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Lecybyl and Hanna
Table 6. Tools for assessment of BTP.
Table 7. Principles of BTP management.
•   Breakthrough pain assessment algorithm
•   Implementing primary therapies
(developed by portenoy R)
(surgery, radiotherapy, chemotherapy)
•  episodic pain documentation sheet (Zappatello 2002)
•   Optimising around the clock medication
•   Breakthrough pain questionnaires (Portenoy 1990) with
(long acting medication)
later modifications
•   Specific pharmacological interventions
(short acting, ‘recue’ medication)
Table 8. Treatment options for BTP.
•  Physical
    •  Rubbing/massage
    •  Application of heat
    •  Application of cold
    •  TeNS (transcutaneous electric stimulation)
    •  Distraction
    •  Relaxation
    •  Hypnotherapy/hypnosis
•  Pharmacological
    •  Modification of the background analgesic regimen
        •  Increase dose of analgesic
        •  Using stronger analgesic
        •  Opioid rotation
        •  Addition of another analgesic
        •  Addition of co-analgesic (predominantly: anticonvulsants, antidepressant)
    •  Use of breakthrough (‘rescue’) analgesic
        •  Non opioid analgesic: Paracetamol, NSAID, Ketamine, Nitrous oxide
        •  Opioid analgesics: Morphine, fentanyl, diamorphine, codeine, hydrocodeine
        •  Other medication (e.g. midazolam—BTP due to muscle spasm)
•  Invasive procedures
    •  Nerve blockade
        •  Peripheral nerve blokade
        •  Single injection of local anaesthetics
        •  Single injection of local anaesthetics with adjuvant (e.g. corticosteroids)
        •  Continous peripherial nerve/plexus blockade
    •  Neuroaxial nerve blokade
        •  epidural injection/infusion
        •  Intrathecal injection/infusion
    •  Surgical procedures (e.g. surgical stabilization of relevant bone(s) or use of orthotic device)
•  Neuromodulatory
    •  TeNS
    •   Spinal cord stimulation—no data available for BTP, however this technique could deliver analgesia on-demmand,
thus potentially could be effective for BTP
    •   Accunpuncutre—it is postulated that acupuncture can provide acute and prolonged pain relief. There is no data
about efficacy of acupuncture for BTP
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Breakthrough pain
Table 9. Specific treatments for different types of breakthrough pain.
•  Incident pain
    •  Pre-emptive use of a short acting opioid 30 minutes before activity
    •   Initially use the same as the four-hourly dose of normal-release morphine (approximately 16% of the daily dose)
when necessary
    •  Titrate the dose of rescue medication
•  Idiopathic/spontaneous
    •  Oral transmucosal fentanyl citrate (OTFC) was shown to be an effective treatment for breakthrough pain
•  end of dose failure
    •  Alter the around the clock medication to increase the dose
used to treat BTP. At other times an opioid such as
Advantages and disadvantages of the oral route
a controlled or sustained release morphine product
for BTP management12,15,41,45–47 are summarized in
is used for background pain and a transmucosal fen-
Table 11. Alternative routes of administration was
tanyl is used for breakthrough pain.12
proposed: oral transmucosal5,l4,37,42,43,48,Intravenous,49
Traditionally, it was recommended to use a fixed
Subcutaneous,50 Intranasal,51 and Intrapulmonary.52
ratio of the total daily dose of opioids to treat the
breakthrough pain.41 Randomize trials have demon-
Fentanyl Buccal Tablets
strated that there is no correlation between the dose
The fentanyl buccal tablet (FBT; Fentora®, Frazer, PA,
of opioid needed to control background pain and the
Cephalon Inc.) is a novel delivery system for fentanyl
dose of OTFC needed to control the breakthrough
citrate. Fentanyl is a well studied, highly lipophylic,
pain.37,42,43 Thus, the dose of breakthrough pain medi-
µ-opioid agonist. The toxicological, pharmacologic
cation should be titrated in the same manner as dose
effects and mechanisms of action of fentanyl are well
of background medication.15 That is, the background
characterized. FBT utilizes the oral transmucosal route
pain medication and the BTP medication should be
of administration. The advantages/disadvantages of
titrated independently. The World Health Organiza-
transmucosal route of administration45,53 are presented
tion (WHO) guidelines promote the use of the oral
in Table 12. Transmucosal absorption allows fentanyl
route for the management of cancer pain.44 There
to bypass first-pass cytochrome P450 3A4 (CYP3A4) -
route has the highest patient acceptability for route of
mediated gastrointestinal and/or hepatic metabolism
administration.45 The oral route is usually effective for
and allow more fentanyl to enter the systemic circula-
the treatment of background pain; however, there are
tion compared with gastrointestinal absorption of oral
significant disadvantage of the oral route for break-
fentanyl.54,55 FBT utilizes OraVescent (r) technology
through pain management. The oral route is associated
to improve bioavability and speed of transmucosal
with delayed onset of action (∼20–30 minutes for oral
delivery. At the site of administration FBT produces
morphine),46 delayed peak effect (∼60 minute for oral
an effervescent reaction which causes a pH decrease
morphine)15 and long duration of action (∼3–6 hours).46
followed by a pH increase. These changes of pH are
hypothesized to optimize pill dissolution and mem-
brane permeability facilitating rapid absorption.54–56
Table 10. Features of ideal ‘rescue’ medication for break-
This rapid absorption should decrease the time to
through pain.
onset of analgesia making FBT highly suitable for
•  Good efficacy
the management of breakthrough pain.57 Properties of
FBT are summarized58 in Table 13. The effect of FBT
•  Rapid onset of action
has been studied out to 2 hours and analgesic effect
•  Short duration of action
has been shown to persist for the 2 hour study period.
•  Minimal adverse effects
In studies on cancer pain FBT has demonstrated a
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Lecybyl and Hanna
Table 11. Oral route for BTP ‘rescue’ medications.
•  Advantages of oral route
    •  Familiar/acceptable for patients and healthcare professionals
    •  Convenient for patients and healthcare professionals
    •  Large variety of opioid drugs and formulation available
    •  Cost effective
•  Disadvantages of oral route
    •  Not suitable for patient suffering for
        •  Dysphasia
        •  Nausea
        •  vomiting
        •  Dysfunction of upper gastrointestinal tract
    •  variation in oral bioavability
    •  Slow onset of action (∼20–30 minutes for oral morphine)
    •  Delayed peak effect (∼60 minute for oral morphine)
    •  Long duration of action (∼3–6 hours)
    •   Some oral preparation contain alcohol (e.g. Oromorph oral solution 10 mg/5 ml) which makes them unsuitable
for use in patients with certain religious beliefs
Table 12. Transmucosal route of administration for BTP management.
•  Advantage of transmuccosal route
    •  Acceptable and convenient to patients
    •  Acceptable to health care professionals
    •  Suitable for patients which can’t use oral medications (dysphasia, vomiting, nausea, dysfunction of upper GI tract)
    •  Potentially fast onset of action
    •  Avoidance degradation by gastric acid and gastric enzymes
    •  Avoidance of first pass metabolism
    •  Cost effective than certain other (invasive) routes of administration
•  Disadvantages
    •  Required special formulation (OTFC, OraVescent technology)
    •  Not suitable for patient with
      •  Dryness of mouth
      •  Oral pathology
      •  Severe disability (cannot agitate the preparation)
      •  Severe fatigue (cannot agitate preparation)
    •  Limited number of suitable medication and formulation
    •  variation in oral transmuccosal bioavailability
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Breakthrough pain
Table 13. Fentanyl bucal tablet.
Mechanism of action
Fentanyl is a well studied, highly lipophylic, µ-opioid agonist. The novelty of this compound is a new trans-mucosal
delivery system called OraVescent®.
pharmacokinetics
  •  After application fentanyl from Fentanyl Buccal Tablet (FBT) is rapidly absorbed.
  •  AUC0-t and Cmax are linearly proportional to dose up to dose equal 800 µg.
  •  Lack of bioequivalence of four 100 µg tablet with one 400 µg. Probably due to differences in tablet surface.
  •  Steady state is reached with 5 days for FBT 400 µg administrated every 6 hours.
  •  The mean ratio of the multiple dose/single dose Cmax is equal 2.0.
  •   Direct PK comparison of FBT vs. OTFC showed shorter Tmax (median Tmax 47 vs. 91 minute respectively) and
better bioavailability: FBT = 65% vs. OTFC = 47%).
Clinical efficacy
Greater efficacy vs. placebo was proved for BTP episodes associated with cancer, low back and neuropathic pain.
65% of cancer patients, 81% of low back pain patients and 78% neuropathic pain patients were able to identify effective
dose of FBT for BTP at open label titration phase.
Majority of low back patients (56%) reach highest available dose of FBT (800 µg) during titration phase.
Higher doses than 800 µg dose is not exist. we assume that this is related to a lack of PK linearity above this dose.
13% of cancer BTP episodes, 20% low back pain episodes and 23% of neuropathic pain episodes achieved 33%
improvement of pain intensity in 15 minutes.
60 minutes after medication administration efficacy (defined as % BTP episodes with 33% improvement of pain
intensity) was equal 75% for cancer patient (placebo = 48%) and 58% for low back patient (placebo = 26%).
easy of administration comparing with iv route is obvious, however described paradigm of buccal administration could
lead to mistakes (e.g. instant swallowing the tablets, not waiting enough time before swallowing…) especial for elderly
population.
Safety and tolerability
FBT is generally well tolerated.
Mild adverse effects are associated with opioid receptor mediated effects or with local effervescent reaction.
Local side effects could accumulate in time when patients will use FBT for long period of time.
Significant number of patient withdrawal from the studies or not achieved pain improvement during titration phase
(43% for cancer BTP study, 29% for low back study, 23% for chronic neuropathic pain study).
There is potential risk of abuse in non-cancer population.
Drug interaction
There is potential interaction with ritonavir. Oral ritonavir might decrease clearance of iv administrated fentanyl by 67%,
resulting in 174% increase in fentanyl AUC .
0–∞
Coadministration of FBT and ritonavir has not been studied, however, an increase in fentanyl AUC is expected.
15 minute onset of action.59 Fentanyl buccal tablets
sublingual/buccal Sulfentanyl62,63 have been reported
(FBT) is novel delivery system for fentanyl citrate.
as being effective in small groups of patients for BTP
FBT utilises OraVescent® technology to improve
treatment. Recently results of intranasal application
bioavailability and speed of drug delivery.
of non-opioid medication for small group of non-
cancer pain patients was published. Intranasal NMDA
Future perspectives
agonist (S)ketamine was succesful in rapid reduction
Alfentanyl and Sufentanyl are the synthetic opioid
of neuropathic pain64 and may therefore be potential
analgesics, chemically similar to fentanyl but with
future medication for BTP.
more rapid onset and shorter duration of action when
Alternate routes of administration could further
given parenterally.60 Sublingual Alfentanyl61 and
improve the efficacy of BTP management. Intranasal
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Lecybyl and Hanna
and intrapulmonary routes are under exploration.
conclusion
The nose can accommodate 150–200 microlitters of
Recently introduced delivery systems for opioid medi-
drug solution in each nostril. A special feature of the
cations represent major improvements in BTP manage-
nasal route is the close association of the brain to the
ment; however, the ideal drug or delivery system for
olfactory area and the unique physiology of this area
BTP management is still an unfulfiled. The time to peak
(i.e. an absence of the normal blood-brain barrier):
analgesia of the new rapid onset opioids, such as FBT, is
this may enable a fraction of the drug to enter the
still longer than the time to peak pain of many BTP epi-
intrathecal space directly.65
sodes. Thus, the ideal BTP medication is yet to be found.
Intranasal fentanyl spray (INFS) was inves-
Studies are needed to expand our knowledge about the
tigated in phase III, double blind, randomised,
different patho-physiological mechanisms involved in
placebo controlled, crossover, multicenter trial.
BTP and to help us understand the variability of BTP
INFS was titrated to an effective dose (50, 100
within the individual patient. If the intensity of BTP is
or 200 microgram). Efficacy (compared with pla-
variable within the individual patient, the initial dose
cebo) as well as safety and tolerability was dem-
titration paradigm used to define the effective analgesic
onstrated.66 INFS was also directly compared with
dose of BTP medication could be inappropriate, being
OTFC in open-label, randomised, crossover trial.
too high for some BTP episodes and too low for others.
INFS demostrated faster median time to onset
The ideal BTP medication would provide dosing ver-
of ‘meaningful’ pain relief compared to OTFC67
satility to address this intra-patient variability of BTP
(Table 14). Interestingly, there was only a weak
intensity. New fentanyl delivery systems offer theoreti-
association between effective INFS doses and
cal advantages over short acting (regular release) oral
effective OTFC doses.67
morphine and patients seem to prefer the rapid onset
Several explorative studies have looked at the
opioids over morphine for BTP management. Studies
use of intranasal opioids for the treatment of break-
that directly compare a rapid onset fentanyl preparation
trough pain: fentanyl, morphine, diamorphine, and
(FBT) and oxycodone are underway in the USA. More
alfentanyl12 have been studied and this route appears
studies that compare rapid onset opioids and standard
promising. Some agents may not be amenable for
drugs like morphine and oxycodone regular release
nasal administration, for example, methadone admin-
(short acting) in diverse patient populations are needed
istrated by intranasal route caused a burning sensa-
to help us define the full benefit of matching the time
tion in healthy volunterers.68
course of action of the analgesic to the BTP.
A case report (two patients) of BTP successfully
treated with intrapulmonary fentanyl administration
Disclosures
was published.52 This route may offer a speed of onset
This manuscript has been read and approved by all
rivaling intravenous drug administration due to rapid
authors. This paper is unique and is not under con-
access to the circulation via the pulmonary capillary
sideration by any other publication and has not been
bed. Further studies are needed to define the role of
published elsewhere. The authors report no conflicts
intrapulmonary medications in the management of
of interest.
breakthrough pain.
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