Pain management

C. I. Ripamonti
*
Supportive Care in Cancer Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, Italy
Despite published guidelines and educational programs on the assessment and treatment of cancer-related pain, in
any stage of oncological disease, unrelieved pain continues to be a substantial worldwide public health concern either
in patients with solid and haematological malignancies. The proper and regular self-reporting assessment of pain is the
rst step for an effective and individualized treatment. Opioids are the mainstay of analgesic therapy and can be
associated with non-opioids drugs such as paracetamol or non-steroidal anti-inammatory drugs and to adjuvant
drugs ( for neuropathic pain and symptom control). The role and the utility of weak opioids (i.e. codeine,
dihydrocodeine, tramadol) are a controversy point. Morphine has been placed by World Health Organization on its
Essential Drug List. In the comparative study with other strong opioids (hydromorphone, oxycodone), there is no
evidence to show superiority or inferiority with morphine as the rst choice opioid. Oral methadone is a useful and safe
alternative to morphine. Methadone presents the potential to control pain difcult to manage with other opioids.
Although the oral route of opioid administration is considered the one of choice, intravenous, subcutaneous, rectal,
transdermal, sublingual, intranasal, and spinal routes must be used in particular situation. Transdermal opioids such as
fentanyl and buprenorphine are best reserved for patients whose opioid requirements are stable. Switching from one
opioid to another can improve analgesia and tolerability.
Key words: assessment, bone pain, cancer pain, neuropathic pain, prevalence, treatment
introduction
Pain is an unpleasant sensory and emotional experience
associated with actual or potential tissue damage or described
in terms of such damage [1]. Pain is both a sensation
(conscious awareness of a noxious stimulus) and an emotional
experience (intense feelings of displeasure resulting in a pattern
of reactive behaviour). The perception of the intensity of pain
is dependent on the interactions between nociceptive and non-
nociceptive impulses in ascending pathways, as well as the
activation of descending pain-inhibitory systems. Cancer pain
may be acute, chronic, and episodic. From a pathophysiological
point of view, pain can be classied as nociceptive (somatic
and visceral), neuropathic (central, peripheral, sympathetic)
idiopathic, or psychogenic [2].
prevalence
Pain prevalence ranges from 64% in patients with metastatic,
advanced, or terminal phase disease, 59% in patients on
anticancer treatment, and 33% in patients after curative
treatment [3]. In the 18 studies reporting the pain severity,
one-third of the patients rated their pain as moderate to severe
[3]. No difference in pain prevalence was found between the
patients during anticancer treatment and those in advanced or
terminal phase of the disease. In patients on oncological
treatments, the most frequent causes of pain are painful
peripheral neuropathy, radiation-induced brachial plexopathy,
chronic pelvic pain secondary to radiation, post-surgical pain
[4]. Pain has a high prevalence in specic cancer types such as
pancreatic (44%) and head and neck cancer (40%) [5].
Moreover, nearly half of the cancer patients were under-
treated with a high variability across study designs and clinical
settings. Recent studies conducted both in Italy and in Europe
[6, 7] conrmed these data, showing that pain was present in
all phases of cancer disease (early and metastatic) and was not
adequately treated in a substantial percentage of patients,
ranging from 56% to 82.3%. In prospective study [8], the
adequacy of analgesic care of cancer patients was assessed by
means of pain management index in 1802 valid cases of
in- and outpatients with advanced/metastatic solid tumour
enrolled in specically devoted to cancer and/or pain
management (oncology/pain /palliative centres or hospices).
The study showed that patients were still classied as
potentially under-treated in 25.3% of the cases
(range 9.8%55.3%).
Contrary to the percentage of incidence of pain of
haematological patients reported in the literature years ago
(i.e. 5% with leukaemia and 38% with lymphoma), a
substantial proportion of patients with haematological
malignancies may suffer from pain not only in the last months
of life (83%) [6, 9] but also at the time of diagnosis and during
active therapies (67.3%) [9, 10]. According to the World
Health Organization (WHO), the incidence of cancer was 12
*Correspondence to: Dr C. I. Ripamonti, M.D. Supportive Care in Cancer Unit,
Fondazione IRCCS, Istituto Nazionale Tumori, Via Venezian n 1, 20133 Milano, Italy. Tel:
+39-02-2390-3644-3383-3641; Fax: +39-02-23904847; E-mail: carla.ripamonti@
istitutotumori.mi.it
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symposium article
Annals of Oncology 23 (Supplement 10): x294x301, 2012
doi:10.1093/annonc/mds360
The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com

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667 470 new cases in 2008 and based on the projections, it will
be >15 million in 2020 [11].
These statistics suggest that cancer-related pain may be a
major issue of health care systems worldwide.
pain assessment
Pain is always a subjective sensation; it is what the patient says
it is [1] and may be affected by emotional, social, and spiritual
components; thus, it has been dened as total pain.
Individualized pain management should take into account
the onset, type, site, duration, intensity, and temporal patterns
of the pain (from this, it is often possible to dene the cause of
the pain), concurrent medical conditions, and, above all, the
subjective perception of the intensity of pain that is not
proportional to the type or to the extension of the tissue
damage but depends on the interaction of physical, cultural,
and emotional factors.
The assessment of pain is based on the expression of pain as
reported by the patients referred to the previous 24 h or at the
moment of the evaluation and includes pain at rest and pain
on movement. The proper and regular self-reporting
assessment of pain (intensity and outcomes) with the help of
validated assessment tools is the rst step for an effective and
individualized treatment. The most frequently used
standardized scales [12] are visual analogue scales, verbal
rating scale (VRS), and the numerical rating scale (NRS;
Figure 1). Observation of pain-related behaviours and
discomfort is indicated in patients with cognitive impairment
to assess the presence of pain. The assessment of all
components of suffering such as psychosocial distress should
be considered and evaluated.
treatment
principles of pain management
An effective pain-relieving therapy [1317] must considering
the following issues:
Inform the patients about pain and pain management and
encourage them to take an active role in their pain
management.
Prevent the onset of pain by means of the by the clock
administration, taking into account the half-life,
bioavailability and the duration of action of the different
drugs; thus, analgesics for chronic pain should be prescribed
on a regular basis and not on as required schedule.
Prescribe a therapy which is simple to be administered and
easy to be managed by the patient himself and his family,
particularly when the patient is cared for at home. The oral
route appears to be the most suitable to meet this
requirement, and, if well tolerated, it should be advocated as
rst choice.
Prescribe a rescue dose of a short- or immediate-release
medication (as required) other than the regular basal opioid
therapy to manage episodic pain [also called breakthrough
pain (BTP)]. The type of rescue opioid medication may be
the same of the type of medication taken on regular intervals
or may be different according to the drug availability and the
efcacy and tolerability of the short release formulation.
Tailor the dosage, the type and the route of drugs
administered according to each patients needs. The dose of
the analgesic drugs is inuenced by the intensity of pain and
has to be promptly adjusted to reach a balance between pain
relief and side effects. The rescue doses taken by the patients
are an appropriate measure of the daily titration of the
regular doses.
Consider an alternative route for opioid administration when
the oral administration is not possible because of severe
vomiting, bowel obstruction, severe dysphagia, or severe
confusion as well as in the presence of poor pain control,
which requires rapid dose escalation and/or in the presence
of oral opioid-related adverse effects.
Prevent and treat the possible opioid-related adverse effects
such as nausea, vomiting, and constipation.
A number of clinical studies have conrmed the effectiveness
of this approach, in >90% of patients whatever the social
cultural environment was [18].
pharmacological treatment
According to the published guidelines [1315], opioids are the
mainstay of analgesic therapy and are classied according to
their ability to control the mild to moderate pain (codeine,
dihydrocodeine, tramadol, dextropropoxyphene; second step of
the WHO analgesic ladder) and to control the moderate to
severe pain (morphine, methadone, oxycodone,
buprenorphine, hydromorphone, fentanyl, heroin, levorphanol,
oxymorphone; third step of the WHO analgesic ladder).
Opioid analgesics can be combined with non-opioid drugs
such as paracetamol or with non-steroidal anti-inammatory
drugs (NSAIDs) [19] and with adjuvant drugs [20]. Non-
opioid drugs are effective for treating mild pain. Paracetamol
[19] and NSAIDs are universally accepted as part of the
treatment of cancer pain at any stage of the WHO analgesic
ladder at least in the short-term and unless contraindicated.
The long-term use of NSAIDS or Cox-2 selective inhibitor has
to be carefully monitored and reviewed periodically because
Figure 1. Validated and most frequently used pain assessment tools.
Annals of Oncology
symposium article
Volume 23 | Supplement 10 | September 2012 doi:10.1093/annonc/mds360 | xi,

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they can provoke severe gastrointestinal bleeding and renal
insufciency.
Although the role of strong opioids is universally
recognized in the treatment of moderate to severe pain, there is
no common agreement regarding the role and the utility of the
second step of the WHO analgesic ladder (weak opioids for
mild to moderate pain) [19, 2123]. No substantial differences
in pain relief between non-opioids alone and non-opioids plus
weak opioids have been reported in a meta-analysis of data
from published randomized controlled trials [23]. Different
results were obtained by Moore et al. [24] in a systematic
review of randomized controlled trials on analgesia obtained
from single oral doses of paracetamol alone and in
combination with codeine in post-operative pain. They found
that 60 mg codeine added to paracetamol produced worthwhile
additional pain relief even in single oral doses.
The role and the utility of the second step of the WHO
analgesic ladder have been debated by various authors.
Controversial points regarding the use of the second step are
that (i) there are insufcient data regarding the effectiveness of
the so-called weak opioids; (ii) there are few studies showing a
real advantage in their use compared with strong opioids; (iii)
the second-step drugs are often marketed in combination with
a non-opioid such as paracetamol, aspirin, or NSAID, and it is
the latter component that limits the dose; and (iv) these drugs
are often expensive in respect to their potential benets
(costbenet ratio) [25].
Moreover in routine clinical practice, the question that arises
is Is there any difference in pain control and/or tolerability
using weak opioids in respect to low dose of strong opioids in
managing mildmoderate pain? Unfortunately, not robust data
are available to solve the question.
In few studies with a small number of patients, low dose of
oral morphine in respect to weak opioids was a reliable method
of mildmoderate pain management in opioid-nave advanced
cancer patients [26, 27]. However, further research is necessary.
Data supporting the role of modied two-step analgesic
ladders or oral tramadol as an alternative to codeine/
paracetamol are insufcient to recommend their routine use in
cancer patients with mild to moderate cancer pain [28].
Since 1977, oral morphine is used by hospices and palliative
care units as the drug of choice for the management of chronic
cancer pain of moderate to severe intensity, because it provides
effective pain relief, is widely tolerated, simple to administer,
and comparatively cheap. The WHO expert committee
introduced morphine as a major pain-relieving drug and has
strongly asserted the necessity of making it available all over
the world. Morphine is considered the gold standard step III
opioid [13, 14] and was placed by WHO on its Essential Drug
List. Ideally two types of formulations are required: normal-
release morphine (NRM; for dose titration) and sustained
release (for maintenance treatment) [2931].
Although, some clinicians indicate no differences in using
sustained release or NRM when initiating oral strong opioids
therapy for pain control [32], it is clinically suggested that the
best approach is to tailor the dosage of the opioid to the needs
of the individual patients, starting treatment with oral NRM,
because its dosage can be modied very quickly (also every
hour) according to the patients needs [2931]. This strategy
may be used to titrate and retitrate the opioid dosage to
achieve pain relief individually even on a day-by-day basis.
Once an effective morphine dosage is achieved by using
NRM, one may switch to a sustained-release oral preparation
or to a transdermal opioid using a dosage conversion
guidelines. For patients with severe pain is necessary to
consider intravenous titration (dose nding) with morphine.
Table 1 shows three different approaches [3335].
Recently, systematic reviews of other strong opioids such as
hydromorphone and oxycodone were published [36, 37].
Both drugs are analogues of morphine with similar
pharmacodynamics properties [38] and can be considered as
an alternative to morphine in the treatment of moderate to
severe cancer pain; however, there is no evidence that
demonstrated superiority or inferiority compared with
morphine as the rst choice opioid.
Oral methadone is considered to be a useful alternative to
oral morphine. Methadone is characterized by a large inter-
individual variation in pharmacokinetics and by rapid and
extensive distribution phases (half-life of 23 h) followed by a
slow elimination phase (beta half-life of 1560 h) that may
cause accumulation if doses are too large or the dosing
intervals are too short over a long period of time. This is the
main reason why attention is required when using this drug for
the treatment of chronic cancer pain. However, respiratory
depression has never been reported by the authors who studied
methadone in cancer patients [3842]. Methadone has the
potential to control pain that does not respond to morphine or
other opioids, because methadone shows incomplete cross-
tolerance with other mu-opioid receptor agonist analgesics.
Moreover, there is the possibility of using it instead of other
opioids such as morphine, when accumulation of active
metabolite is the cause of side effects such as myoclonus,
sedation, confusion, nausea, and vomiting. Methadone is a
more potent opioid than believed. The dose ratio between
methadone and morphine varies from 1:4 until 1:14 according
to the dose of morphine previously administered. For this
reason, caution is recommended when switching from any
opioid to methadone particularly in patients who are tolerant
to high doses of opioids [3842].
Although the oral route of opioid administration (the
one of choice) is effective in most situations, intravenous
(i.v. or e.v.), subcutaneous (SC), rectal, transdermal (TTS),
sublingual, intranasal, and spinal administration must be
considered in particular situation (Table 2) [38].
Fentanyl citrate has a very high analgesic potency (75 times
more than morphine), is skin compatible having a low-
molecular weight with good solubility and thus suitable for
transdermal administration. Transdermal fentanyl offers the
advantage of providing up to 3 days continuous administration
of a potent opioid, avoiding the use of syringes and expensive
drug-infusion pumps for the treatment of cancer pain. The use
of transdermal fentanyl is not indicated in opioid-naive patients,
during the opioid titration phase and to control BTP. When
switching from one opioid to transdermal fentanyl, the patient
has to continue taking 50% of previous opioid dose during the
rst 24 h [43]. There is some clinical and preclinical evidence
showing that transdermal fentanyl produces less constipation
when compared with morphine and other strong opioids [44].
symposium article
Annals of Oncology
xio | Ripamonti Volume 23 | Supplement 10 | September 2012

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Transdermal fentanyl and transdermal buprenorphine are
not indicated during the titration period and are best
reserved for patients whose opioid requirements are stable.
They are an alterative treatment of choice to
subcuntaneous and intravenous continuous infusion of
opioids for patients who are unable to swallow, patients
with poor tolerance of morphine, and patients with poor
compliance. Moreover, buprenorphine has a role for
Table 1. Intravenous titration (dose nding) with morphine for severe cancer pain
Authors (ref.) Study design and patients population Initial morphine dosage and
route
Following dosage and
route
Results
Radbruch
et al. [33]
Prospective study. Twenty-six
inpatients with uncontrolled pain, on
step II opioids.
i.v. PCA pump programmed
for 24 h: 1 mg bolus,
lockout interval of 5
0
.
Maximum dose of 12 mg/
h.
Oral SR morphine q12 h;
dose on the basis of the
previous i.v.
requirements.
i.v.PO conversion 1:2.
BKP treated with i.v.
PCA until stable
analgesia was reached.
Mean pain intensity (NRS 0100):
at entry: 67;
after 5 h: 22;
at day 7: 17;
at day 14: 12.
Mean morphine dosage (i.v. PCA) in
the rst 24 h: 32 mg (range 478).
Mean daily morphine dosage
(PO + i.v. PCA for BKP) at PCA
termination (range 26 days): 139
mg (range 20376).
Mean morphine dosage (PO) at day
14: 154 mg (range 20344).
No substantial adverse events.
Mercadante
et al. [34]
Prospective study. Forty-ve inpatients
with severe (NRS 7) and prolonged
pain. At entry, 30 patients were on
step II opioids, 15 were on step III
opioids.
i.v. bolus (2 mg every 2
0
)
repeated until analgesia or
adverse effects were
reported.
Oral SR morphine; dose
on the basis of the
previous i.v.
requirements.
i.v.PO conversion: 1:3
for lower i.v. dosages,
1:2 for higher i.v.
dosages.
The same i.v. dose was
maintained for BKP in
the rst 24 h.
Mean pain intensity (NRS 010).
At entry: 8.1.
After 9.7
0
: 3.0 with a mean i.v.
morphine dosage of 8.5 mg.
Mean daily oral morphine dosage at
time to discharge: 131 mg (107156)
+ 10.8 mg (i.v. extra doses).
No substantial adverse events.
Harris et al.
[35]
RCT.
Sixty-two strong opioid-nave
patients.
Pain intensity NRS 5.
Patients were randomized to receive
i.v. morphine (n = 31) or oral IR
morphine (n = 31).
i.v. group:
1.5 mg bolus every 10
0
until pain relief (or
adverse effects).
Oral group:
IR morphine 5 mg every
4 h in opioids-naive
patients.
10 mg in patients on
weak opioids. Rescue
dose: the same dose every
1 h maximum.
i.v. group:
Oral IR morphine q4
h, on the basis of the
previous i.v.
requirements.
i.v.: PO conversion 1:1.
Rescue dose: the same
dose every 1 h
maximum.
Oral group: follow the
same scheme.
Percentage of patients achieving
satisfactory pain relief:
after 1 h: i.v. group, 84%; oral group,
25% (P < 0.001);
after 12 h: i.v. group 97%; oral group
76% (P < 0.001);
after 24 h: i.v. group and oral group
similar.
i.v. group: median morphine dosage
(i.v.) to achieve pain relief: 4.5 mg
(range 1.534.5). In the same group,
mean morphine dosage (PO) after
stabilization: 8.3 (range 2.530) mg.
Oral group: median morphine
dosage to achieve pain relief: 7.2
(2.515) mg.
No substantial adverse events.
i.v., intravenous; PCA, patient-controlled analgesia; SR, slow release; IR, immediate release; NRS, numerical rating scale; step II of the WHO analgesic
ladder; BKP, breakthrough pain.
Annals of Oncology
symposium article
Volume 23 | Supplement 10 | September 2012 doi:10.1093/annonc/mds360 | xi,

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Table 3. Conversion tables between different opioids
(A) Conversion fentanyl / morphine (B) Conversion fentanyl TTS-methadone
Oral release
morphine
24 h
Parenteral
morphine
(Ev o Sc) 24 h
Fentanyl
TTS*
Fentanyl
TTS
Oral
methadone
60 mg 20 mg 25 mcg/h 25 mcg/h = 0.6 mg X 20 = 12 mg methadone/day
90 mg 30 mg 50 mcg/h 50 mcg/h = 1.2 mg X 20 = 24 mg methadone/day
120 mg 40 mg 75 mcg/h 75 mcg/h = 1.8 mg X 20 = 36 mg methadone/day
180 mg 60 mg 100 mcg/h 100 mcg/h = 2.4 mg X 20 = 48 mg methadone/day
(C) OTFC -oral morphine
OTFC 200 60 mg oral morphine
OTFC 400 120 mg oral morphine
OTFC 600 180 mg oral morphine
OTFC 800 240 mg oral morphine
(D) Conversion morphine - methadone
Slow release oral
morphine 24 hours
or Equivalent
Parenteral morphine
Dose ratio when:
*Adverse effects
Pain under
control
Dose ratio when:
*uncontrolled pain
**Tolerance
Dose ratio when:
*Uncontrolled pain
**Adverse effects
3090 mg 4:1 4:1 + 33% 4:1 + 20%
90300 mg 8:1 8:1 + 33% 8:1 + 20%
300600 mg 12:1 12:1 + 33% 12:1 + 20%
600 mg 14:1 14:1 + 33% 14:1 + 20%
Table 2. Potential applications of the different routes of opioid administration
Symptoms Oral Sublingual buccal Rectal CSI Intravenous Transdermal
a
Spinal
Vomiting ++ ++ ++ ++ ++ ++
Bowel obstruction ++ ++ ++ ++ ++ ++
Dysphagia ++ ++ ++ ++ ++ ++
Cognitive failure ++ ++ ++
Diarrhoea ++ ++ ++ ++ ++
Haemorrhoids
Anal ssures ++ ++ ++ ++ ++ ++
Coagulation
Disorders ++ ++ ++ ++ ++
Severe
Immunosuppression ++ ++ ++ ++ ++
Generalized oedema ++ ++ ++ ++ ++
Frequent dose changes ++
a
++ ++# ++# +
Titration ++ ++ + ++# ++#
Breakthrough pain ++
b
++ ++ ++# ++#
+, may be indicated; ++, is indicated; , is contraindicated.
a
Fentanyl.
b
Only immediate-release formulations, # = patient-controlled analgesia, PCA.
CSI, continuous subcutaneous infusion.
symposium article
Annals of Oncology
xi8 | Ripamonti Volume 23 | Supplement 10 | September 2012

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patients with renal impairments and undergoing
haemodialysis treatment [1544].
switching the opioid and/or the route of
administration
In clinical practice, we can observe patients treated with oral
morphine or another opioid who present with an imbalance
between analgesia and side effects. In particular, some clinical
situations may be present: (i) pain is controlled, but there are
some intolerable adverse effects for the patient; (ii) pain is not
adequately controlled and it is impossible to increase the
opioid dose because of adverse effects; or (iii) pain is not
adequately controlled notwithstanding the continuous increase
of the opioid dose, which does not produce adverse effects.
According the data of literature, different therapeutic
strategies may prevent or treat adverse effects: (i) general
measures (reduce the opioid dose, hydrate the patient, correct
abnormal biochemistry if present, reduce the number of
comedication); (ii) administration of drug to relief symptoms/
side effects caused by other medications (such as antiemetics,
laxative etc.); (iii) administration of the opioids by an
alternative route; (iv) administration of an alternative opioid;
or (v) switching to both an alternative opioid and route
[38, 41, 4549].
Data are not available to allow us to compare the advantages
and disadvantages of the different therapeutic strategies such as
the use of drugs to relieve the symptom(s), the switching of
opioid, and/or the route of administration.
Patients who have poor analgesic efcacy or tolerability with
one opioid will frequently tolerate another opioid well,
although the mechanisms that underlie this variability in the
response to different opioids are not known. The selection of
an alternative opioid is largely empirical. A pure opioid agonist
such as oxycodone, methadone, hydromorphone, and fentanyl
is recommended when morphine fails. Positive results in
symptom control and pain relief were also obtained by
switching the route of opioid administration. Dose ratio
between different opioids has to be considered when opioid
switching is performed (Table 3) [38, 41, 4549].
neuropathic pain
Although neuropathic pain (NP) is considered frequent in
cancer patients and difcult to manage with opioids, only few
studies on the prevalence of NP are available [20]. A 1-month
follow-up prospective epidemiological multicenter study was
carried out to assess the prevalence of NP and to evaluate its
management in 46 oncological units in Spain during a mean
period of 4 weeks [50]. At baseline, physicians prescribed
opioids to 88% of patients and oxycodone was the most
frequent used (74%) followed by fentanyl (46%), morphine
(22%), tramadol (38%); non-opioid analgesic treatment to 67%
of patients with NSAIDs as the most frequent (71%), and co-
adjuvants with gabapentin as the most frequent (52%). After 1
month, pain intensity decrease was similar among the different
types of primary tumour, but it was substantial in patients with
metastases (P < 0.01) versus patients with no metastases. The
changes in pain intensity were signicantly different (P < 0.05)
among treatment groups, with oxycodone showing the largest
reduction.
The study is particularly interesting due to the high number
of cancer patients on active oncological therapies screened for
NP in oncological units.
pancreatic pain
In patients with painful inoperable pancreatic cancer opioid
analgesics and celiac plexus neurolysis are two therapeutic
options for pain management. In a meta-analysis of studies on
the endoscopic ultrasound-guided (EUS) celiac plexus
neurolysis (CPN), the reduction of pain was observed in 80%
of patients [51]. Wyse et al. [52] randomized 98 patients with
conrmed assessable pancreatic adenocarcinoma diagnosed by
the EUS-guided ne-needle aspiration cytology, to early EUS-
CPN or conventional pain management. The intensity of pain
by a seven-point Likert scale, the opioid consumption
(morphine equivalent) and the QoL scores were assessed at
1 and 3 months. Compared with conventional analgesic
therapy administered alone, the difference in mean percent
change in pain score was greater after 1 month and
substantially (P = .01) greater at 3 months in patients treated
with early EUS-CPN who had also a trend in reduction of
analgesic drugs consumption.
breakthrough pain
BTP is dened a transitory are of pain that occurs on a
background of relatively well controlled baseline pain [53].
The typical BTP episodes are of moderate to severe intensity,
rapid in onset (minutes), and relatively short in duration
(median 30 min) [53]. A systematic literature review shows that
there is not widely accepted denition, classication system or
well validated assessment tools for cancer-related BTP [54],
and the setting of care [55]. These ndings could explain why
the prevalence is reported with a wide range from 19% to 95%
[55]. Available pharmacological treatment options include oral,
transmucosal, buccal, oral immediate-release morphine
sulphate (IRMS), or nasal opioids; however, few RCTs are
available [5658]. However, only seven RCTs that were
founded, ve studies were placebo-controlled studies that
evaluated oral transmucosal fentanyl citrate (OTFC), intranasal
fentanyl spray (INFS), fentanyl buccal tablet, one trial
compared OTFC with IRMS [59], and one trial compared
INFS with OTFC [60].
Recently, a fentanyl pectin nasal spray (FPNS) was developed
to optimize the absorption prole of fentanyl across the nasal
mucosa: A RCT trial showed that FPNS provides superior pain
relief compared with placebo [58]. The effects on pain are
present after only 5 min after a dose with further signicative
reductions from 10 min after a dose [58]. The same results were
found by Davies et al. [61] who studied the consistency of
efcacy, tolerability, and patient acceptability of FPNS versus
IRMS in 110 patients experiencing one to four BTP episodes/
day during a background pain treatment with oral morphine or
equivalent opioids 60 mg/day. A statistically signicant
differences in pain intensity scores and in pain relief in favour
of FPNS versus IRMS by 10 min after the administration
(P < 0.05) were found. Overall acceptability scores were
Annals of Oncology
symposium article
Volume 23 | Supplement 10 | September 2012 doi:10.1093/annonc/mds360 | xi

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substantially greater for FPNS than for IRMS at 30 (P < 0.01)
and 60 (P < 0.05), respectively. Most of the patients were
satised/very satised with the convenience (79.8%) and easy
to use (77.2%) of FPNS. Nobody reported substantial nasal
effects.
In a prospective, multi-center phase IV study [62],
sublingual fentanyl orally disintegrating tablet (ODT) was
studied in 181 patients. During the study, 3163 episodes of
BTP were treated with a mean dose of 401.4 cg per episode.
In respect to baseline, a substantial improvement of maximum
BTP intensity appeared with sublingual fentanyl ODT (P <
0.0001) within 5 min of administration in 67.7% of episodes
and maximum effect within 30 min in 63% of episodes.
Quality of life assessed by means of the modied pain
disability index and emotional distress assessed by HADS
substantially improved during the observational period of 28
days. The drug was well tolerated.
conclusions
Physical pain is only one potential cause of suffering; thus,
successful pain control requires attention to some or all of the
other aspects of care and suffering, and this requires a
multidisciplinary approach to treatment; failure to do this
frequently results in unrelieved pain.
Successful pain management requires treatment of the
patients total pain: physical, psychological, social, spiritual,
and cultural starting from the diagnosis and through the illness
[63]. All the physicians are involved in the assessment and
treatment of cancer-related pain, because this symptom can be
treated in each setting of care [64, 65].
Each patient has his/her own threshold of pain. Adequate
sleep, elevation of mood, diversion, empathy, and
understanding all can raise an individuals pain threshold.
Alternatively, fatigue, anxiety, fear, anger, sadness, depression,
and isolation can lower the pain threshold.
disclosure
The author has declared no conicts of interest.
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Annals of Oncology
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Volume 23 | Supplement 10 | September 2012 doi:10.1093/annonc/mds360 | xo1

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