Review

Pain management of the

cancer patient
Stephan A Schug† & Chandani Chandrasena
†
1. Introduction The University of Western Australia & Royal Perth Hospital, Perth, Australia

2. Guidelines for treating cancer

Introduction: Cancer pain is one of the most important symptoms of
pain
malignant disease, which has a major impact on the quality of life of cancer
3. Management of breakthrough patients. Therefore, it needs to be treated appropriately after a careful
pain assessment of the types and causes of pain.
4. Use of co-analgesics and Areas covered: The mainstay of cancer pain management is systemic pharma-
adjuvants cotherapy. This is, in principle, still based on the WHO guidelines initially
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Gazi Univ. on 01/03/15

5. Conclusions published in 1986. Although these have been validated, they are not evi-
6. Expert opinion dence-based. The principles are a stepladder approach using non-opioids,
weak and then strong opioids. In addition, adjuvants can be added at any
step to address specific situations such as bone or neuropathic pain. Patients,
even if they are on long-acting opioids, need to be provided with immediate-
release opioids for breakthrough pain. In case of inefficacy or severe adverse
effects of one opioid, rotation to another opioid is recommended.
Expert opinion: There is a major need for more and better randomized
controlled trials in the setting of cancer pain as the lack of evidence is hamper-
ing the improvement of current treatment guidelines.
For personal use only.

Keywords: cancer pain, co-analgesics, non-opioids, opioids, WHO guidelines

Expert Opin. Pharmacother. (2015) 16(1):5-15

1. Introduction

Cancer is a multifaceted complex condition affecting physical, psychological, social

and spiritual aspects of the life of an individual affected by it. Out of all accompanying
symptoms, cancer pain has been recognized as one of the most important ones [1].
A multidisciplinary evidence-based approach is recommended for its treatment,
including pharmacological treatments, psychosocial and behavioral interventions,
physical therapy and exercise, interventional procedures and spiritual support [2-4].

1.1 Prevalence
Nearly 10 million patients are being diagnosed with cancer annually with an ever-
increasing incidence [5,6]. Cancer patients present in 20 -- 50% of cases with pain
as a symptom [7]. The prevalence of cancer pain depends on the localization and
type of cancer; cancers of the head and neck show the highest pain prevalence of
70%. The prevalence increases with progression of cancer and may reach 90% in
terminal patients [8]. Pain is also common in cancer survivors with a reported
prevalence of 26 -- 54% [7].

1.2 Undertreatment of cancer pain

Despite a plethora of guidelines and recommendations, cancer pain still is often
undertreated [9]. According to systemic reviews of the literature, nearly half of the
patients in pain do not receive adequate treatment [10]. Morphine consumption
data and the pain management index are two indicators, derived from World
Health Organization (WHO) guidelines, that have been utilized to assess the effi-
cacy of cancer pain treatment; recent studies using these methodologies continue
to find undertreatment of cancer pain in multiple settings [9].

10.1517/14656566.2015.980723 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 5

All rights reserved: reproduction in whole or in part not permitted
 S. A. Schug & C. Chandrasena
Article highlights.
. Cancer pain is the most important symptom of
malignant disease.
. Cancer pain is commonly undertreated.
. The treatment of cancer pain should follow validated
established guidelines.
. Beside opioid analgesics as the mainstay, non-opioids
and co-analgesics play an important role in the
pharmacological management of cancer pain.
. Despite all progress, the evidence base for cancer pain
management remains limited and future better studies
addressing multiple areas of uncertainty are required.
This box summarizes key points contained in the article.
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It is important to identify the reasons for this situation so
that deficiencies can be addressed, ultimately leading to
improved quality of care and thereby quality of life of cancer
patients. Patients’ beliefs such as fear of addiction and of possi-
ble side effects of analgesics, misconceptions of pain meaning
disease progression, beliefs that treatment of disease is more
important than that of pain are some of the contributing factors
for not seeking adequate pain treatment [11]. Healthcare pro-
viders such as medical practitioners and nurses play a key role
For personal use only.
in the delivery of pain management. Here physicians’ lack of
knowledge about cancer pain management, inadequate pain
assessment and inadequate opioid prescription as well as again
fear of causing addiction need to be addressed to achieve better
quality of care [12]. System and institutional factors include
inadequate referral to appropriate specialties, unavailability of
or limited access to certain analgesics, in particular opioids,
and inadequate allocation of funds to palliative care [12].
1.3Characteristics of cancer pain
The causes of pain in cancer patients can be classified as:
1) directly related to cancer, for example, direct invasion
or compression of structures by the cancer;
2) related to cancer therapy, for example, due to surgery,
chemotherapy or radiotherapy;
3) related to effects of cancer, such as bed sores or debility;
4) other, often age-related, comorbidities such as chronic
back pain or osteoarthritis in patients with cancer.
With current advanced cancer therapy, patients’ sur-
vival has increased, and as a result, previous cancer
patients present increasingly with such issues.
From a therapeutic approach, it is important to classify pain
as either nociceptive or neuropathic. Nociceptive pain is
defined as ‘pain that arises from actual or threatened damage
to non-neural tissue and is due to the activation of nociceptors
(International Association for the Study of Pain Taxonomy at:
http://www.iasppain.org/Education/Content.aspx?Item-
Number=1698&navItemNumber=576) The pain originat-
ing form somatic structures is described as localized, sharp,
6 Expert Opin. Pharmacother. (2015) 16(1)
throbbing pain or pressure sensation, whereas visceral pain is
described as dull, aching, cramping and diffuse type of
pain [1]. Neuropathic pain is defined as ‘pain caused by a lesion
or disease of the somatosensory nervous system’. Cancer-
related neuropathic pain could be related to cancer compress-
ing or infiltrating nerves as well as related to cancer therapy.
For example, nearly 90% of patients receiving neurotoxic che-
motherapy experience chemotherapy-induced peripheral neu-
ropathy [13]. Patients commonly complain of shooting,
tingling or burning type of pain, accompanied by sensory def-
icits in the painful area as well as paresthesia, hyperalgesia and
allodynia. Often neuropathic pain may coexist with nocicep-
tive pain, then commonly called ‘mixed’ pain.
1.4 Cancer pain assessment
Currently, there are a number of validated cancer assessment
tools that can be applied according to the clinical con-
text [14,15]. Because cancer pain is a multidimensional experi-
ence, a comprehensive systematic assessment addressing all
domains plays a significant role in cancer pain management.
The assessment has to be ongoing, complete and documented.
Particular attention should be focused towards the functional
assessment of these patients. The ongoing multidimensional
assessment has to be multidisciplinary, involving other rele-
vant specialties in patients care. Clinical practice guidelines
developed by the National Comprehensive Cancer Network
provide a comprehensive tool for this purpose [1,16].
The severity of pain is assessed either by visual analog scale,
numerical rating scale or verbal rating scale. More complex
assessment can be performed using the brief pain inventory
and McGill Short Form Questionnaire [17,18].
It is of note that most cancer patients have multiple pains,
either at different sites or of different origin (e.g., inflamma-
tory and neuropathic) [19]. It is important to consider this
fact when assessing pain, as it will influence treatment strate-
gies. A number of rather specific individual pain syndromes
have been described and these may need to be recognized [20].
Breakthrough pain is acute exacerbation of pain of short
duration on the background of stable pain, commonly con-
trolled with opioids [21]. A comprehensive assessment of
breakthrough pain, encompassing the etiology, intensity,
mechanisms and impact on patients’ daily activities should
be performed [21]. Assessment tools for the assessment of
breakthrough pain are under development; the Breakthrough
Assessment Tool is currently at initial validation stage and
may become a useful tool in pain assessment [22].
For cognitively impaired patients, assessment tools such as
the Abbey pain scale can be applied [23]; furthermore, observa-
tion of behavioral patterns is useful [18].
2. Guidelines for treating cancer pain
The original guidelines, published by the WHO in 1986 [24]
and updated in 1996 [25], have governed and improved cancer
pain relief worldwide and remain an important tool to

improve the current situation, in particular in the developing
world. Although these guidelines are not evidence-based, their
value in clinical practice is well validated [26,27]. According to
these guidelines, overall cancer pain management is based on
pharmacological methods as the mainstay and non-
pharmacological methods. Pharmacological management is
based on the 3-step analgesic ladder. Step 1 recommends
use of non-opioids for mild pain, step 2 recommends intro-
duction of weak opioids for moderate pain, and in step 3,
strong opioids are introduced for severe pain [18,28]. Among
other issues addressed later in the review, one drawback to
the WHO stepladder approach is that drug choices are based
on severity of pain only, but does not provide guidance to
dosing strategies and temporal variations of pain.
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The non-pharmacological methods such as physical, psy-
chological and complementary therapies are outside the scope
of this paper [18]. Apart from pharmacotherapy, causal treat-
ment options such as chemotherapy, radiotherapy, immune
therapy or surgical interventions should be considered as com-
ponents of the pain management strategy; this may require
referral and involvement of appropriate other specialties [29].
Multiple organizations have recently published guidelines for
the management of cancer pain [30]; the European Society of Med-
ical Oncology most recently updated its guidelines [10]. In addi-
For personal use only.
tion to analgesics recommended by WHO analgesic ladder,
these guidelines highlight the role of adjuvant analgesics, pharma-
cological management of opioid-related side effects and use of
other non-pharmacological methods. Guidelines like these should
govern contemporary cancer pain management. Assessment of
outcome should not only focus on the provision of pain relief
alone; a simple guidance to outcome assessment should look at
the so-called four As (analgesia, activity, adverse effects and addic-
tion), commonly used in non-cancer pain settings.
Pharmacotherapy for mild cancer pain
2.1
(WHO step 1)
For the treatment of mild cancer pain, non-opioids such as
aspirin, acetaminophen (paracetamol) and NSAIDs are used.
NSAIDs, in particular, are recommended as first-line therapy
for bone pain [31].
2.1.1 Acetaminophen
Acetaminophen has antipyretic and analgesic properties.
There is currently increasing discussion on the limited efficacy
of paracetamol and the possibly underestimated adverse
effects [32]. In a systematic review, insufficient evidence was
found to support the use of acetaminophen in combination
with strong opioids [33]. Of particular concern are increasing
reports of hepatic toxicity with paracetamol, particularly at
doses more than 4 g/day. Most of these overdoses are uninten-
tional and related to multiple analgesics containing acetamin-
ophen and to acetaminophen/opioid combinations and have
resulted in FDA advice on dose restrictions [34]. Certain anti-
cancer drugs and paracetamol may interact to cause increased
hepatotoxicity [1].
Expert Opin. Pharmacother. (2015) 16(1)
Pain management of the cancer patient
2.1.2 NSAIDs
NSAIDs inhibit cytokines and chemokines, which are media-
tors of inflammation, in addition to their inhibitory effects on
biosynthesis of prostaglandins [35]. This group of drugs exerts
analgesic effects on the central and peripheral nervous system;
details are still under evaluation [1]. COX, the enzyme blocked
by NSAIDs, has two isoenzymes labeled COX-1 and COX-2.
COX-1 is primarily a constitutive enzyme, responsible for
synthesis of protective prostaglandins that maintain integrity
of gastric mucosa and platelet function as well as partially per-
fusion of compromised kidney. COX-2 is primarily inducible
and mediates pain and inflammation, but is also protective in
the kidney [28]. The analgesic properties of NSAIDs are dose-
dependent and have a ceiling effect; however, with increasing
dosage, there is an increase in the incidence of side effects
without a ceiling effect [36]. There is no evidence for one
NSAID being superior to another, but rotation may be useful
in case of poor efficacy; non-selective NSAIDs have similar
efficacy to COX-2 selective ones [37]. It is useful to combine
NSAIDs with acetaminophen, as the efficacy of the combina-
tion is superior to each drug used on its own [38]. There is
weak support from a systematic review that NSAIDs added
to strong opioids in cancer pain improve analgesia or reduce
opioid requirements [33].
The classical non-selective NSAIDs such as naproxen and
ibuprofen can cause gastric and intestinal ulceration, renal
impairment and platelet inhibition. Substitution with a selec-
tive COX-2 inhibitor such as celecoxib or etoricoxib reduces
the gastrointestinal (GI) toxicity significantly and causes no
platelet inhibition; there may even be a reduced risk of acute
kidney injury with COX-2 selective agents [39]. The assumed
increased risk for cardiovascular complications such as myo-
cardial infarction and stroke with COX-2 inhibitors [1] could
not be confirmed [40]; thromboembolic adverse effects are a
class effect of all NSAIDs, and some COX-2 inhibitors such
as celecoxib are actually safer than some non-selective
NSAIDs such as diclofenac [41].
Even in the elderly, NSAIDs could be an effective treat-
ment option in spite of concerns about their safety profile as
long as contraindications are considered; they should be pre-
scribed at the lowest effective dosage for the shortest possible
duration [42].
Pharmacotherapy for moderate cancer pain
2.2
(WHO step 2)
For the management of moderate cancer pain, the clinical
relevance of the recommendations of WHO analgesic ladder
step 2 to use so-called weak opioids is increasingly being
debated [43,44]. Although the guidelines recommend weak
opioids such as codeine, dihydrocodeine (DHC) and trama-
dol administered orally in combination with non-opioids for
the management of moderate pain, there is increasing support
for the omission of this step and direct progression to low-
dose strong opioids [10]. However, there is ongoing debate
7
 S. A. Schug & C. Chandrasena
on this issue [45]; in many countries, weak opioids are an
important option to treat cancer pain in view of poor access
to strong opioids as outlined above.
2.2.1 Tramadol
Tramadol is a centrally acting atypical analgesic, which inhib-
its re-uptake of serotonin and more importantly noradrena-
line. It is metabolized into O-desmethyl tramadol (M1),
which has µ-opioid receptor agonist activity [46,47]. Tramadol
is usually administered orally, but can be given parenterally or
rectally, if required. Its low abuse potential, worldwide avail-
ability, reduced opioid-related adverse events (e.g., constipa-
tion) and specific activity in neuropathic pain make it the
most useful of the weak opioids [18,48]. However, there is a
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concern that tramadol can precipitate serotonergic symptoms
up to a serotonin syndrome either with significant overdose or
when co-administered with other serotonergic drugs.
2.2.2 Codeine
Codeine is an inactive prodrug of morphine; its analgesic
efficacy relies on liver metabolism by the CYP2D6 enzyme,
leading to its active metabolite morphine. Polymorphisms in
CYP2D6 result in a range of metabolic patterns from ultra-
rapid to ultra-slow metabolizers, who experience anything
For personal use only.
from significant morphine effects (and adverse effects) to no
analgesia at all [1,49]. Further disadvantages are variable oral
bioavailability and a high propensity to induce constipation;
overall codeine is not a useful choice in the setting of cancer
pain, as long as other opioids are available [18].
2.2.3Dihydrocodeine
DHC is a semisynthetic analog of codeine, with an equivalent
potency of 1:3 ratio of subcutaneous DHC to morphine. As it
does not require metabolic conversion [49], it is a more reliable
step 2 weak opioid than codeine, but advantages over low
doses of strong opioids have never been shown.
Pharmacotherapy for severe cancer pain
2.3
(WHO step 3)
Severe cancer pain is commonly treated with strong opioids, if
feasible by oral administration. Opioids are classified as full
agonists, partial agonists, agonist--antagonists or antagonists
according to their interaction with opioid receptors. Opioids
with full agonist properties do not show ceiling effect for anal-
gesia and dose increase is limited by side effects. Opioids with
either agonist--antagonist or partial agonist properties have
ceiling effect for analgesia; therefore, they may not be ideal
for cancer pain management [28]. There is no evidence of
one opioid agonist being superior to another with regard to
efficacy [1].
2.3.1 Strong opioids used in cancer pain treatment
2.3.1.1 Morphine
Morphine is a pure opioid agonist available as oral immediate
(IR) or controlled release (CR) preparations (12 or 24 h
8 Expert Opin. Pharmacother. (2015) 16(1)
duration of effect) and for subcutaneous, intramuscular and
intravenous (i.v.) administration as well as rectal administra-
tion in most countries. The half-life of IR preparations is
2 -- 3 h with 20 -- 30% bioavailability following oral adminis-
tration. The oral to parenteral conversion is about 3:1 [50].
Morphine is metabolized in the liver into morphine-
6-glucuronide (M6G), an active metabolite having analgesic
properties exceeding those of morphine itself and morphine-
3-glucuronide (M3G), devoid of analgesia. M6G accumula-
tion in renal failure can cause increased adverse effects and
potentially respiratory depression. The neurotoxic and hyper-
algesic effects of M3G may be responsible for reduced efficacy
and increased adverse effects with escalating dosages of mor-
phine. Genetic variability in morphine metabolism may play
a role in the manifestation of these effects [28,50], but the
effects are also influenced, as are those of all other opioids,
by genetic variants of the OPRM1 gene, encoding the
µ-opioid receptor [51].
2.3.1.2 Oxycodone
Oxycodone is a synthetic opioid with comparatively high
k-receptor affinity; the clinical relevance of this effect is
debated. A brain:plasma ratio of 3:1 of unbound drug
explains why oxycodone has relative less affinity for µ recep-
tors than morphine, but a higher potency [52]. It is available
in oral IR and CR formulations as well as for parenteral use.
Oxycodone has a bioavailability of 60 -- 87% following oral
administration. The half-life of IR oxycodone is about
2 -- 3 h. Although oxycodone is metabolized in liver into nor-
oxycodone and oxymorphone, analgesia is mainly attributable
to the parent drug. The side effect profile of this drug is sim-
ilar to morphine, although it causes less nausea, vomiting,
pruritus and hallucinations [1,18,49]. Constipation is one of
the known adverse effects of opioids and often refractory to
conventional treatment in cancer patients. Combination
preparations of slow-release naloxone and slow-release oxyco-
done provide analgesia and reduce constipation at the same
time. When administered orally, naloxone acts primarily on
GI opioid receptors reducing the constipating effect of oxyco-
done. However, due to an extremely high first-pass effect, it
has very low oral bioavailability and does not antagonize the
analgesic effect of oxycodone in the CNS. Two recent studies,
one in cancer patients and the other in non-cancer chronic
pain patients, show that this combination was well tolerated
by both groups, with significantly less GI complications and
similar analgesic profile to oxycodone [53,54]. There is a recom-
mended daily maximum dose of 80 mg to avoid systemic nal-
oxone effects. In severe hepatic failure, naloxone may no
longer undergo significant first pass metabolism and may con-
sequently antagonize central opioid receptors, impairing the
analgesic effect of oxycodone [6].
Hydromorphone
2.3.1.3
Hydromorphone is a semisynthetic opioid with mainly
µ-agonist activity. It is 5 -- 10 times more potent compared

to morphine and therefore particularly useful, when adminis-
tration of smaller volumes is preferred, as in subcutaneous
infusion. The half-life is about 2.5 h. CR preparations are
available [55]. Hydromorphone is metabolized in the liver
mainly to hydromorphone-3-glucuronide (H3G) and small
amount of 6-hydroxy-hydromorphone. H3G may cause neu-
rotoxic side effects, particularly when retained in patients with
impaired renal function and following prolonged use [49].
2.3.1.4 Fentanyl
Fentanyl is a lipophilic µ-receptor agonist, 100 times more
potent than morphine. Due to extensive first-pass metabo-
lism, oral administration is ineffective. However, different
formulations for other routes of administration are available:
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parenteral as well as transdermal and transmucosal such as
intranasal and sublingual [56]. There may be a reduced side-
effect profile compared to morphine (nausea, vomiting,
constipation, sedation and pruritus), in particular with trans-
dermal use [57]. Fentanyl is metabolized by CYP3A4 into inac-
tive metabolites; thus it is a safe option in patients with renal
impairment [58]. For breakthrough pain, IR preparation with
rapid response, such as oral transmucosal fentanyl or intrana-
sal fentanyl spray, is available [59]. Intranasal fentanyl is partic-
ularly useful due to its rapid uptake, even in patients with dry
For personal use only.
mouth [21].
2.3.1.5 Methadone
Methadone is a µ- and d-opioid receptor agonist, but also an
NMDA receptor antagonist and a noradrenaline and seroto-
nin reuptake inhibitor [60]. These properties might explain
the benefits some patients achieve when rotated from other
opioids to methadone and possibly its efficacy in neuropathic
pain. The pharmacokinetics are complicated by large interin-
dividual variability of the plasma half-life and is 15 -- 60 h; it
takes about 2 -- 5 days before steady-state plasma levels are
reached. Due to this, dose escalation should be done care-
fully [60]. In high doses, it may provoke cardiac dysrhythmias
due to QT prolongation [61]. Compared to morphine, it
causes less nausea, vomiting and constipation. Methadone is
metabolized in the liver and GI tract into inactive metabolites.
Drugs commonly used in cancer patients such selective sero-
tonin reuptake inhibitors (SSRIs), ketoconazole, omeprazole
can potentiate methadone by inhibiting cytochrome enzymes
(mainly CYP2B6) involved in its metabolism [62]. The inac-
tive metabolites are eliminated via GI tract and kidneys,
thus making it safer in patients with renal impairment. Meth-
adone may become an opioid of choice for patients on
dialysis [63]. Because of complex pharmacokinetics and equia-
nalgesic conversion variability, prescribing should be done by
experts [1,18,49].
Buprenorphine
2.3.1.6
Buprenorphine is an opioid agonist-antagonist that is about
100 times more potent than morphine. Sharing features
inherent to this group of drugs, it has potentially a ceiling
Expert Opin. Pharmacother. (2015) 16(1)
Pain management of the cancer patient
effect, but only at extremely high doses. Buprenorphine can
be given by the sublingual (as low oral bioavailability), trans-
dermal or parenteral route and can substitute high doses of
other opioids contradicting previous concerns [64]. Buprenor-
phine is metabolized in liver to active metabolites and
excreted through GI tract, thus making it safe in patients
with renal impairment. Compared to other opioids, it has bet-
ter side effect profile in terms of nausea, vomiting and consti-
pation and a lower risk of respiratory depression [65].
Although there is increasing use of buprenorphine in cancer
pain, data are still limited [66], but suggest potential advan-
tages, for example, over transdermal fentanyl [67].
2.3.1.7 Tapentadol
Tapentadol is centrally acting novel synthetic opioid devel-
oped for the management of mild-to-moderate pain [68] and
has been used successfully in cancer pain [69]. It has less affin-
ity for µ-receptors compared to strong opioids and inhibitory
effects on central norepinephrine reuptake. Despite an opioid
receptor affinity 20 times less than that of morphine in
humans, a recent prospective study has shown a conversion
ratio of 1:3.3 between oral morphine and tapentadol bidirec-
tionally [70]. The reduced µ-receptor affinity confers less
opioid-related side effects, mainly of GI origin (nausea, vom-
iting and constipation) than equianalgesic doses of conven-
tional opioids [68]. The monaminergic effects support the
concept of superior efficacy in neuropathic pain [71].
Other opioid agonists such as meperidine (pethidine) and
propoxyphene are not recommended for cancer pain manage-
ment due to neurotoxicity of their metabolites. Partial ago-
nists are not suitable as well due to their inherent ceiling
effect for analgesia [1].
2.3.2 Practical management of strong opiods
There is ongoing debate on the method to initiate opioids in
cancer pain management, but only limited evidence to sup-
port one single approach. Opioid titration using sustained
release oxycodone and IR morphine has been supported in
pilot studies [72]. Subsequent to the titration phase, dosage is
adjusted according to patient’s response. Conventionally, the
dose increment is calculated 33 -- 50% of average total daily
dosage during the preceding few days [73]. Transdermal
opioids are recommended as second-line therapy when oral
administration is not applicable. In spite of recommenda-
tions, the selection of an opioid is governed by factors such
as clinicians’ experience, patients’ prior experience, cost and
availability of specific opioids [73].
2.3.2.1 Opioid rotation
Opioid rotation or opioid switching describes the process of
substituting a strong opioid in step 3 with another strong opi-
oid [74]. The process is aimed to increase either opioid efficacy
or reduce adverse events of opioids. The effectiveness of
another opioid may be due to the phenomenon of incomplete
cross-tolerance or the presence of variable responses at
9
 S. A. Schug & C. Chandrasena
multiple µ-receptor subtypes [75]. For dose calculation of
equivalency, conversion tables are being used; however, these
are based on data derived from studies on acute pain set-
tings [76]. Such tables need to be used with caution due to
the interindividual variability of response to opioids; to min-
imize the risk of overdose, dose reduction and clinical
judgment is important. A careful approach taking into consid-
eration other confounding factors such as associated medical
and psychological factors has been proposed [77].
3. Management of breakthrough pain
Breakthrough pain is defined as episodic bursts of pain of
short duration on the background of stable pain controlled
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by opioids. Guidelines recommend comprehensive assessment
followed by individualized plan for the pain manage-
ment [45,78]. IR opioid preparations are recommended as the
first-line therapy for breakthrough pain. Advantages of IR
opioid preparation are ease of administration, relatively fast
onset of analgesia and quite extensive experience in their
use. Morphine, oxycodone, hydromorphone, buprenorphine
and methadone are available as IR preparations [21]. The other
options are intranasal or transmucosal fentanyl [56,59] and i.v.
morphine. Studies have demonstrated the efficacy of intrana-
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sal fentanyl over transmucosal preparation [45]. Intranasal fen-
tanyl has a high bioavailability (70 -- 90%) and peak plasma
levels are reached in about 13 min following administra-
tion [21]. Two recent meta-analyses showed that transmucosal
fentanyl preparations are more efficacious than oral morphine
in this setting [79,80].
Additionally non-opioid pharmacotherapy such as acet-
aminophen, NSAIDs, bisphosphonates, clonidine and keta-
mine lozenges may be useful. In addition, guidelines
recommend application of non-pharmacological methods
such as radiotherapy, surgical interventions and regional
techniques [78].
4. Use of co-analgesics and adjuvants
These are medications not commonly regarded as analgesics
but can be used to enhance the effect of primary analgesics
or in certain selected situations as primary analgesics. Co-
analgesics are used, in particular, in specific diagnoses or clin-
ical scenarios such as neuropathic pain, bone pain or visceral
pain. These drugs can be incorporated into each step of the
analgesic ladder depending on the clinical situation to achieve
optimum pain relief and relief from symptoms. Adjuvants
may have other indications apart from achieving analgesia,
which should be taken into consideration during prescription.
4.1 Antidepressants
Antidepressants play an important role in the management
of neuropathic pain conditions. Tricyclic antidepressants
(TCAs) such as amitriptyline or nortriptyline and selective
serotonin--norepinephrine reuptake inhibitors (SNRIs) such
10 Expert Opin. Pharmacother. (2015) 16(1)
as duloxetine or venlafaxine are commonly in use. SSRIs
such as fluoxetine have limited application in neuropathic
pain due to low efficacy [81].
4.2 Tricyclic antidepressants
TCAs are generally considered first-line therapy in neuro-
pathic pain, also in cancer patients. They are very effective
in a number of different neuropathic pain settings such as
pain arising from nerve compression and infiltration and
post-chemo- and radiotherapy [81]. The numbers-needed-to-
treat (NNTs) for TCAs in neuropathic pain are in the range
of 2.1 -- 2.8 [13]. As a group, they inhibit reuptake of norepi-
nephrine and serotonin thereby enhancing descending inhib-
itory pathways of pain with additional effects on NMDA
receptors and sodium channels [81]. The antidepressant effects
may be additionally beneficial, particularly in cancer patients,
who are more prone to depression; furthermore amitriptyline
enhances the antihyperalgesic effects of co-administered mor-
phine [82]. The analgesic dose required is less than the antide-
pressant dose. TCAs have anticholinergic properties causing
dry mouth, blurred vision and in high doses can cause cardiac
dysrhythmias, conduction abnormalities, narrow-angle glau-
coma and prostatic hyperplasia. As a result, TCAs are often
not suitable for elderly patients and poorly tolerated [1,13,28];
they should be started at low doses at night to improve com-
pliance. Abrupt discontinuation of higher doses of TCAs may
cause withdrawal symptoms [81].
4.3 Serotonin--norepinephrine reuptake inhibitors
SNRIs are showing promising results in the treatment of
cancer-related neuropathic pain [31,81]. Compared to TCAs,
these have a better side-effect profile. Both venlafaxine and
duloxetine have also been found to be effective for hot flushes
in patients on hormonal therapy for breast cancer. Duloxetine
interacts with concomitantly administered tamoxifen, reduc-
ing the efficacy of the anticancer medication [1].
4.4 Anticonvulsants
Anticonvulsants are another group of medications that have
become established as first-line treatment of neuropathic
pain. The evidence is limited for older anticonvulsants such
as carbamazepine, phenobarbital and phenytoin with the
exception of carbamazepine in trigeminal neuralgia. These
are also hepatic P450 enzyme inducers and interact thereby
with certain anticancer therapies and steroids, which are
metabolized by the same system. In general, anticonvulsants
are used for neuropathic pain at the same dosage as for
management of seizures [28].
4.5 Gabapentin and pregabalin
Gabapentin and pregabalin are the two anticonvulsants with
the best evidence base for the treatment of neuropathic pain.
Both act as modulators of the a2d subunit of voltage-gated
calcium channels presynaptically, thereby inhibiting excit-
atory neurotransmitter release. For both drugs, NNTs for

neuropathic pain range from 4.2 to 6.4 [13]. Gabapentin given
orally has low bioavailability and shows non-linear pharmaco-
kinetics with increasing dose due to saturation of the transport
mechanism. Pregabalin is more potent, better absorbed and
has a linear pharmacokinetic profile [31,81]. Both these drugs
are primarily excreted unmetabolized through the kidney
and have minimal drug interactions. Dosages have to be
reduced in renal failure. Common side effects are somnolence,
dizziness, peripheral edema and weight. Both drugs are also
effective in chemotherapy- or radiotherapy-induced mucositis
and have significant anxiolytic properties [13,28,31].
4.6 Topical agents
Topical agents for the treatment of neuropathic pain include
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Gazi Univ. on 01/03/15
lidocaine and capsaicin [13]. Lidocaine 5% patches were devel-
oped for post-herpetic neuralgia, but are also effective in other
localized neuropathies, in particular those accompanied by
allodynia [13,31]. The major advantage is the lack of systemic
side effects; local skin irritation following application may
be the only relevant complication. Capsaicin, acting on the
vanilloid receptor TRPV1 was again found be effective for
post-herpetic neuralgia, when applied as a high-concentration
patch (8%) [81].
For personal use only.
4.7 Corticosteroids
Corticosteroids are widely used as co-analgesics in cancer
patients [81]. They are indicated to alleviate pain in spinal
cord compression, superior vena cava syndrome, raised intra-
cranial pressure headache, metastatic bone pain, hepatic cap-
sular distension and neuropathic pain. Relieved pressure due
to anti-inflammatory effects is the most likely mechanism of
action. Apart from analgesia, corticosteroids have been used
in cancer patients to improve appetite and mood and as an
antiemetic. Dexamethasone has been preferred due to its
reduced mineralocorticoid activity, long duration of action
and potency [81]. With prolonged use, patients have to be
monitored for the well-known complications such hypergly-
cemia, peptic ulcers, cushingoid habitus and neurological
complications [1,83].
4.8 Ketamine
Ketamine as an NMDA receptor antagonist is widely used in
cancer pain. Ketamine can be administered parenterally (i.v.
or subcutaneously), but there are also increasing reports on
oral, intranasal and transmucosal administration [84]. There
is contradictory data on its efficacy; a recent randomized con-
trolled trial (RCT) may have failed due to inappropriate
patient selection [85]. Use in increasing doses may be limited
by psychomimetic adverse effects and potential other toxicity.
4.9 Cannabinoid
Cannabinoid use for therapeutic purposes in neuropathic pain
remains controversial with contradictory results on efficacy
and potential abuse [50]. However, there are some positive
results in neuropathic pain caused by cancer and a nasal spray
Expert Opin. Pharmacother. (2015) 16(1)
Pain management of the cancer patient
is licensed in some countries [13]. Other benefits are a potent
anti-emetic effect and improvement of appetite.
4.10 Bisphosphonates
Bisphosphonates are beneficial in cancer-related bone pain, in
particular prostate and breast cancer [81]. They inhibit osteo-
clastic activity and hence bone resorption, but further research
is needed to identify the most useful compound and
treatment schedule [86-88].
4.11 Denosumab
Denosumab, a human monoclonal antibody against receptor
activator of nuclear factor kappa-B ligand (RANKL), has
been shown to reduce bone loss [18]. Positive outcome has
been seen in early studies on patients with bone metastases,
who have been treated with denosumab. Compared to
bisphosphonates, denosumab has better analgesic profile,
prevents skeletal-related events and less adverse effects [89].
5. Conclusions
Cancer pain remains one of the most important and most
distressing symptoms of malignancy. The management of
this symptom requires proper assessment of the patient and
should establish a pain diagnosis. Often pain occurs in multi-
ple locations and can have multiple causes and mechanisms.
Treatment of cancer pain relies primarily on systemic phar-
macotherapy and is based on guidelines, initially developed
by the WHO and then fine-tuned in recent years. Although
there is increasing evidence in certain areas of cancer pain
management, overall treatment is still based on recommenda-
tions that rely primarily on weak data and expert opinion.
However, this approach has resulted in successful treatment
in many patients. Future developments should focus on a bet-
ter evidence base for the guidelines, but also on better access
to medications and appropriate therapies in the developing
world.
6. Expert opinion
The key problem with the whole issue of cancer pain manage-
ment is the lack of definitive evidence in many areas. This is
most obvious with regard to the WHO guidelines, which
were developed on the basis of expert opinion. Although
they have been validated and proven to be effective in a large
number of patients, there is a significant lack of scientific evi-
dence supporting many of the concepts including the
stepladder approach.
For example, the European Palliative Care Research
Collaborative attempted to support the concept of combining
opioids, a common clinical practice, by a meta-analysis [90].
However, the authors were only able to identify two studies
on relatively low evidence levels, which resulted in a weak rec-
ommendation with caveats. The reason is the lack of any RCT
examining the issue of combining opioids.
11
 S. A. Schug & C. Chandrasena

Similar issues can be found in many other key areas of
cancer pain management [91]. The notion, that morphine is
the first-line opioid for cancer pain treatment, repeated in
guideline after guideline, might need to be revised, but good
data are lacking. Similarly, possibly even more disappointing,
dosing recommendations for treatment of breakthrough pain
have not been established in RCTs. Again, all recommenda-
tions in guidelines are primarily based on expert opinion [91].
This list can be continued; the role of COX-2 inhibitors and
the choice of co-analgesics in neuropathic pain states have not
been established on the basis of RCTs in cancer pain, but only
based on results in patients with benign conditions. Even the
optimal treatment of bone pain is currently not based on
proper scientific evidence and any recommendations on
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Gazi Univ. on 01/03/15
addressed. Last but not the least, there remains the key ques-
tion if step 2 is actually really a useful step or if it should not
be omitted in favor of low doses of strong opioids [45]. This
has led some authors to question if the step 2 is only a ‘didactic
instrument’ [43] or an ‘educational substitute for morphine’ [92].
In 2014, we are not closer to an answer to these questions; this
was recently again expressed in an European Association for
Palliative Care guideline publication that stated ‘The utility
of step II opioids in the WHO method has been addressed in
three trials, all of which have significant methodological flaws,
insufficient statistical power, and selection bias.’ [45].
Overall, shortage of RCTs remains the key concern here.
This is to a large extent a result of the difficulties of perform-
ing RCTs in a cancer pain population. The reasons for this are

choice of compound, doses and treatment intervals are again
primarily based on expert opinion.
Another example is the concept that non-opioids should be
continued when opioids are started is supported primarily by
literature from acute post-operative pain management, where
the concept of multimodal analgesia is well established and
supported by RCT and meta-analyses. However, the setting
of chronic cancer pain is very different in many aspects.
Here the data are very limited and evidence-based guidelines
can only make weak recommendations on the usefulness of
For personal use only.
obvious and include difficulties in standardizing treatments
over often heterogeneous patient populations, ethical issues
of enrolling cancer pain patients in yet another clinical trial,
the difficulties of identifying appropriate comparators and
the multiple other symptoms in cancer patients.
Nevertheless, continuing attempts need to be made to
design and perform proper RCTs answering key questions
in cancer pain management to permit better evidence-based
guideline development in the future.

non-opioids in the cancer pain setting [45].

One of the completely unresolved issues in cancer pain
treatment is the role and relevance of the step 2 of the
WHO ladder, that is, the use of so-called weak opioids.
Already the term ‘weak opioids’ is poorly defined, the separa-
tion from strong opioids arbitrary and a specific pharmacody-
namic differentiation does not exist. Furthermore, advantages
of one weak opioid over another have not been properly eval-
uated; the question of ceiling effects has also not been
Declaration of interest
The Anaesthesiology Unit of the University of Western
Australia, but none of the authors personally, has received
research and travel funding and speaking and consulting
honoraria from bioCSL, Bionomics, Eli Lilly, Grunenthal,
Janssen, Mundipharma, Pfizer, Phosphagenics and iX
Biopharma within the last 2 years.

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Expert Opin. Pharmacother. (2015) 16(1)
Pain management of the cancer patient
Affiliation
Stephan A Schug†1,2 MD FANZCA
FPMANZCA &
Chandani Chandrasena3 MBBS FANZCA
†
Author for correspondence
1
Professor, Chair of Anaesthesiology,
The University of Western Australia, School of
Medicine and Pharmacology, Pharmacology,
Pharmacy and Anaesthesiology Unit, Perth,
Australia
2
Consultant Anaesthetist and Director of
Pain Medicine,
UWA Anaesthesiology, Royal Perth Hospital,
Department of Anaesthesia and Pain Medicine,
Level 2, MRF Building, GPO Box X2213, Perth,
6847, Australia
Tel: +61 8 9224 0201;
Fax: +61 8 9224 0279;
E-mail: stephan.schug@uwa.edu.au
3
Senior Registrar and Clinical Lecturer,
Royal Perth Hospital, Department of Anaesthesia
and Pain Medicine, Perth, Australia
15