Download Pharmacological options for the management of refractory cancer pain

Support Care Cancer (2015) 23:1473–1481
DOI 10.1007/s00520-015-2678-9
REVIEW ARTICLE
Pharmacological options for the management of refractory
cancer pain—what is the evidence?
B. Afsharimani & K. Kindl & P. Good & J. Hardy
Received: 21 November 2014 / Accepted: 22 February 2015 / Published online: 7 March 2015
# Springer-Verlag Berlin Heidelberg 2015
Abstract Refractory cancer pain that does not respond to
standard opioid and/or co-analgesic therapy occurs in 10–
20 % of patients. Risk factors include young age, neuropathic
pain type, incident pain, psychological distress, previous opioid use, high tolerance, a history of addiction and impaired
cognition. The management of patients with refractory pain
remains a challenge. Treatment options include opioid manipulation (parenteral delivery, rotation, combination, methadone
and buprenorphine), non-opioids and co-analgesics (paracetamol, non-steroidal anti-inflammatory agents, antidepressants
and anticonvulsants), NMDA receptor antagonists, cannabinoids, lignocaine and corticosteroids. The evidence of benefit
for any of these agents is weak, and each additional agent
increases the risk of adverse events. Evidence-based guidelines cannot, therefore, be developed at present. New approaches are recommended including targeted opioid therapy,
multimodal analgesia, a goal-oriented approach to pain management and increasing use of the multidisciplinary team and
support services.
Keywords Cancer pain . Refractory . Evidence . Analgesia
Introduction
World Health Organisation (WHO) analgesic guidelines recommend a limited number of drugs titrated in a step-wise
B. Afsharimani : K. Kindl : P. Good : J. Hardy (*)
Department of Palliative and Supportive Care , Mater Health
Services, and Mater Research Institute, University of Queensland,
Brisbane, Australia
e-mail: [email protected]
P. Good
St Vincent’s Private Hospital, Brisbane, Australia
fashion according to the severity of pain [1]. These guidelines
are considered the world standard for pain control. It is generally accepted that the use of these guidelines results in the
control of pain in the majority of patients [2].
Refractory cancer pain has been defined as pain related to
cancer or its treatment, of at least 3 months duration, that has
not responded to standard treatment with opioids and coanalgesics [3]. There is no standard definition however, and
cancer pain that is difficult to control has been variously described as difficult, persistent, intractable or opioid nonresponsive in heterogeneous populations exposed to a range
of different medications and interventions. It has been reported to occur in 10–20 % of cancer patients. [4]. The characteristics that lead to difficult pain control are said to include
young age, neuropathic pain type, incident pain, psychological distress, previous opioid use, high tolerance, a history of
addiction and impaired cognition [5]. The prognosis of cancer
pain is reported to be worse in those with mixed pain type,
high pain severity, daily opioid use and poor emotional wellbeing [5]. With the goal of developing evidence-based guidelines for refractory cancer pain management, the evidence for
the treatments and interventions commonly used for refractory
cancer pain was examined.
Methods
Strategies for the management of refractory cancer pain were
obtained from a survey of palliative care physicians [6], from
reviews of refractory cancer pain management [7] and from
personal experience of the authors and palliative care colleagues. Evidence for the effectiveness of each intervention
was sought primarily from the Cochrane data base and from
published systematic reviews searched via Cochrane,
EMBASE, PUBMED and the Joanna Briggs Institute. In the
absence of a formal Cochrane review, systematic reviews,
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randomised and non-randomised controlled trials were accepted. Unless specified otherwise, all trials discussed are
randomised controlled trials (RCTs). The quality of included
studies was not formally assessed or scored. Nonpharmacological interventions including interventional techniques, complementary therapies and psychological support
have not been included and will be the subject of a subsequent
review.
Results
Support Care Cancer (2015) 23:1473–1481
other opioids or routes of administration found subcutaneous
fentanyl to be well tolerated and effective in the management
of refractory pain [21]. In a small retrospective study of cancer
patients who could not tolerate subcutaneous morphine, subcutaneous fentanyl infusion was used to achieve analgesia
with limited side effects [22].
At present, there is no evidence to support the superiority of
parenteral versus oral opioid administration in controlling intractable cancer pain. Based on available evidence, the European Association of Palliative Care (EAPC) recommends the
use of parenteral opioid infusions in cases where oral or transdermal opioids fail to provide effective analgesia [15].
Opioids
Opioids remain the only analgesics with proven benefit in
severe cancer pain [8, 9]. Opioid dose escalation in the face
of increasing pain is often limited by adverse effects. Several
approaches have been proposed to address this including the
proactive and aggressive management of side effects, the use
of co-analgesics, alternative routes of administration or
switching to a different opioid (opioid rotation) [10].
Parenteral opioids
High serum concentrations of opioids can be achieved rapidly
by parenteral administration although the correlation between
serum opioid concentrations and analgesia is poor [11–13].
Clinical studies have shown similar efficacy and tolerability
for both intravenous and subcutaneous delivery [14]. Subcutaneous injection is generally preferred due to ease of administration, but the intravenous route can provide faster pain
relief [15].
Few studies have explored the possibility that refractory
cancer pain responds to a rapid and intensive analgesic intervention. In a small open-label RCT assessing the use of parenteral morphine titration for pain exacerbations, pain was
controlled in 77 % of the cases with no difference between
the subcutaneous and intravenous routes [16]. In patients with
severe pain from advanced cancer, intravenous morphine was
shown to be safe and to result in better immediate analgesia
than oral morphine [17].
The peak onset of action of morphine is seen after about
30 min, even when administered intravenously [18]. More
lipophilic opioids such as fentanyl readily cross the blood
brain barrier and provide effective analgesia more rapidly.
One small RCT studied the benefit of subcutaneous fentanyl
compared to morphine in cancer patients and found both drugs
to be equally efficacious [19]. An uncontrolled observational
study in patients seen in emergency rooms with severe pain
showed fast opioid titration with bolus intravenous fentanyl to
be safe and effective in controlling pain [20]. A retrospective
analysis of cancer patients commenced on subcutaneous fentanyl infusions because of toxicity or uncontrolled pain from
Opioid rotation
Changing or switching from one opioid to another has been
reported in many uncontrolled trials and descriptive studies to
lead to improved pain relief and/or reduction in toxicity. Proposed mechanisms include incomplete cross-tolerance, variation in intrinsic opioid receptor activity, inter and intra-patient
variation in pharmacokinetics/dynamics and relative
desensitisation of opioid receptors [23].
A Cochrane review identified multiple case studies, retrospective reviews and prospective uncontrolled trials all of
which showed benefit [24]. None of the studies was of sufficient quality to be included in a meta-analysis. A subsequent
systematic review identified eleven new trials, of which the
majority showed opioid switching to be highly effective in
controlling cancer pain and reducing adverse effects [25].
All of the studies were of limited quality and lacked
randomisation or controls.
Opioids in combination
Theoretically, patients with pain refractory to a single opioid
might benefit from the addition of a second opioid, especially
when using drugs with different characteristics such as different lipid solubility, routes of metabolism, degree of receptor
activation/antagonism or opioid receptor type affinity. Animal
studies have confirmed the benefit of using a combination of
different opioids in improving analgesia and reducing dependence [26]. Human studies on the benefit of combination opioid analgesia are contradictory. A prospective clinical trial
comparing combination opioid therapy and opioid rotation
in cancer patients with uncontrolled pain showed similar benefit in pain reduction and adverse effects for both manoeuvres
[27]. In contrast, a systematic review on the efficacy and safety of a combination of strong opioids in controlling cancer
pain included two studies that showed better pain relief and
lower side effects when a second opioid was added to the
original [28]. Unfortunately, due to methodological problems
in study design, only a weak recommendation could be made
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towards the use of combination strong opioids in controlling
cancer pain.
Methadone
Methadone is often used as a second-line agent in difficult
pain, instead of, or in conjunction with, other opioids. Inhibition of NMDA receptors and monoamine reuptake plus activation of kappa and delta opioid receptors is postulated to lead
to additional analgesia and reversal of opioid tolerance. Anecdotally, methadone has benefit in patients with predominantly
neuropathic pain [29].
This opioid is difficult to use because of significant interpatient variation in efficacy and unpredictable adverse effects.
Dose titration is complex due to the highly variable pharmacokinetic profile of the drug. Patients must be closely monitored because of the possibility of drug accumulation and
unintended overdose. Methadone is frequently used in the
scenario of opioid rotation or switching. The morphine dose
equivalence of methadone is not clear. It has been suggested
that the morphine-to-methadone equipotent ratio varies depending on the prior dosage of opioids administered, and that
in patients on higher doses of morphine, lower doses of methadone are needed to achieve the same analgesic effect [30].
A Cochrane review of methadone versus opioid comparators included nine RCTs and 459 participants. A number of
different dose and titration schedules were used along with
various pain scales. No superiority over morphine was shown
nor superiority with respect to the treatment of neuropathic
pain. Patients on methadone had a higher rate of withdrawal
due to adverse events [31].
More recently, two RCTs showed a benefit for switching to
methadone. In cancer patients with refractory pain, sustainedrelease morphine, methadone and transdermal fentanyl were
similarly effective in controlling pain, but the need for opioid
escalation was significantly less with methadone [31]. A combination of epidural methadone and lidocaine has been compared to epidural lidocaine alone in cancer patients whose pain
was not adequately controlled with oral morphine. The addition of methadone to lidocaine reduced the need for oral morphine consumption in a dose-dependent manner. This was
improved when epidural dexamethasone was added to the
regimen [32].
The additive effect of acetaminophen on the analgesic efficacy of methadone in cancer patients has been studied. Participants were switched from a stable dose of morphine to
methadone and plus either acetaminophen or placebo. Although acetaminophen showed no advantage over placebo,
switching to methadone significantly improved pain scores,
constipation and xerostomia [33]. Switching to methadone
from other opioid analgesics was also shown to be safe and
effective in a prospective uncontrolled study in 21 opioidtolerant cancer patients [34]. In a prospective uncontrolled
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study in patients with advanced cancer, switching to methadone from oxycodone was successful in improving pain and/
or adverse effects and distress [35].
Methadone may contribute to the management of refractory pain, but to date, there remains considerable uncertainty
regarding dose equivalence, how best to titrate and concern
over potential toxicity.
Buprenorphine
Buprenorphine is a semi-synthetic partial agonist of the mu
opioid receptor with proven efficacy in controlling chronic
pain. In patients requiring escalating doses of opioids for pain
management, buprenorphine may stabilise opioid dosing, provide effective pain relief and improve quality of life (QoL)
[36].
Transdermal buprenorphine has been shown to have a more
favourable adverse effect profile compared to pure mu agonists such as morphine or fentanyl [37, 38]. Buprenorphine
transdermal patches resulted in better analgesia compared to
placebo and rescue buprenorphine in 157 patients with severe
uncontrolled pain from cancer or other disorders [39]. In 137
patients (including 45 cancer patients) with severe chronic
pain, there was a trend towards better pain relief in patients
randomised to transdermal buprenorphine [40]. Compared to
placebo (with rescue analgesia), transdermal buprenorphine
administration resulted in lower pain intensity, less need for
rescue analgesics and fewer discontinuations [41]. In an open
observational surveillance study in 13,179 patients with
chronic pain (including 3690 cancer patients), effective pain
relief, good tolerability and less need for rescue therapy were
seen in patients receiving buprenorphine patches [42].
Compared to sustained-release morphine administration,
transdermal buprenorphine was more effective in providing
long-term pain control and improving QoL in cancer patients
assessed by a randomised prospective study [43].
Buprenorphine is also reported to be effective in controlling neuropathic and breakthrough pain in cancer patients and
to be an option in opioid rotation [37]. Unfortunately, three
systematic reviews have concluded that due to the poor quality
of evidence, a definitive conclusion cannot be made on the
efficacy of this drug in moderate-to-severe cancer pain
[44–46].
Non-opioid analgesics and co-analgesics
The WHO analgesic ladder supports the use of non-opioid
analgesics (paracetamol and NSAIDs) and adjuvant analgesics as monotherapy for mild cancer pain and as adjunct for
improving opioid analgesia in moderate-to-severe pain in cancer patients [47].
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Paracetamol and NSAIDs
Paracetamol and/or NSAIDs are used in patients with cancerrelated pain because of their postulated opioid-sparing effect
[48, 49]. Although effective in mild to moderate cancer pain,
these preparations have limited value in severe pain as dose
escalation is restricted by adverse effects. A Cochrane review
found 14 studies that compared the efficacy of opioids and
NSAIDs or paracetamol, alone or in combination, in cancer
pain. Nine studies showed a slight advantage, one insignificant advantage and four no advantage for combinations of
opioids and NSAIDs/paracetamol over each drug used alone
[50]. A more recent systematic review identified two other
studies that showed a benefit of adding NSAIDs/paracetamol
to an opioid analgesic regimen in cancer patients [48]. One
RCT assessed the outcome of adding oral ketorolac to morphine treatment in patients with advanced cancer. Ketorolac
(60 mg/day) led to better analgesia and reduced the need for
opioid dose escalation [51]. The introduction of dipyrone to a
morphine regimen significantly improved analgesia compared
to placebo in another small RCT [52].
In summary, NSAIDs can have an opioid-sparing effect
and might improve analgesia. However, since clinical studies
are of insufficient number or quality, they can only weakly
support the use of NSAIDs as co-analgesics in the management of cancer pain [48].
Antidepressants
Neuropathic pain accounts for about one third of refractory
pain associated with cancer [5]. Opioid analgesics alone often
fail to control pain completely [7]. Historically, antidepressants have been used as co-analgesics for the management
of neuropathic pain. Any analgesic effect is independent of
the psychological impact and is thought to be due to enhanced
norepinephrine and serotonin-mediated descending inhibitory
output and possibly blockade of sodium channels [53]. The
evidence of benefit in the management of pain comes largely
from trials of non-malignant pain.
A Cochrane review of tricyclic antidepressants in all pain
types suggested that the number needed to treat (NNT) for at
least moderate pain reduction was 3.6. The number needed to
harm (NNH) for minor and major adverse events was 3.7 and
22, respectively. These results are similar to those for the
newer antidepressants such as venlafaxine (NNT=3.1) [54].
A systematic review of amitriptyline showed evidence of benefit in some non-malignant pain scenarios but failed to find
any unbiased well-designed clinical studies to support its use
in cancer pain, [55]. Duloxetine has been shown in three
double-blind RCTs to be effective in controlling diabetic peripheral neuropathic pain [56].
Very few studies have been performed in cancer-related
neuropathic pain. Three small RCTs of venlafaxine [57, 58]
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and amitriptyline [59] in treatment-related neuropathic pain in
cancer patients demonstrated effectiveness. In patients with
advanced cancer, there was no improvement in pain control
when amitriptyline was added to an opioid analgesic regimen
[60]. In pain related to bone metastases, a combination of lowdose antidepressants (imipramine or mirtazapine) with an anticonvulsant (pregabalin) provided better pain control compared to pregabalin alone [61]. There is recent evidence for
the benefit of duloxetine in chemotherapy-induced painful
peripheral neuropathy [62].
A systematic review analysed 14 RCTs and 16 nonrandomised studies of neuropathic cancer pain based on absolute risk benefit and absolute risk harm. Overall, absolute risk
benefit of antidepressants, anticonvulsants, other adjuvant analgesics or opioids outweighed absolute risk harm [63].
Although guidelines recommend using antidepressants for
neuropathic pain especially in cancer patients with mood disorders, rigorous data are lacking to endorse the use of antidepressants as co-analgesics in cancer pain and current practice
is mainly based on clinical experience.
Anticonvulsants
Anticonvulsants, particularly gabapentin and pregabalin, are
commonly used as first-line treatment in neuropathic pain
[64]. Their effect is thought to be exerted through binding to
presynaptic calcium channels, decreasing calcium influx and
neurotransmitter release [65].
A systematic review that analysed five RCTs and three
non-randomised studies on the benefit of combining antidepressants or antiepileptic drugs with opioid analgesics in neuropathic cancer pain found the strongest evidence for the effectiveness of gabapentin [66] although a recent RCT showed
similar analgesic efficacy for both gabapentin and amitriptyline when used as co-analgesics in this setting [67]. In a RCT
in cancer patients, neuropathic pain intensity was significantly
lower in patients treated with pregabalin as compared to placebo [68]. Similarly, pregabalin provided better control of
neuropathic cancer pain compared to placebo, gabapentin or
amitriptyline and reduced opioid consumption [69].
Pregabalin also provides better pain relief and patient satisfaction compared to transdermal fentanyl [70]. High quality controlled trials are still needed to support the safety and efficacy
of these drugs in cancer patients [71].
N-methyl-D-aspartate (NMDA) receptor antagonists
Ketamine is a general anaesthetic agent that is often used at
subanaesthetic doses as a co-analgesic, usually in combination
with opioids, particularly in neuropathic pain [72]. It interacts
with multiple receptors thought to be involved in pain perception. NMDA receptor activation is thought to result in neuronal hyperexcitability and the development of opioid tolerance.
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Ketamine has been used commonly in palliative care for the
management of refractory or difficult pain, usually in combination with opioids [73]. There is great variation in practice
with respect to the type of pain treated with this drug, the dose,
route and frequency of delivery.
A Cochrane review updated in 2012 included two RCTs
that evaluated the effectiveness of adding ketamine to opioids
in cancer patients with refractory pain. Both studies found
ketamine administered intravenously [74] or intrathecally
[75] to be effective in improving analgesia. Pooling of data
was not possible due to the small size and clinical heterogeneity of the studied populations. The review concluded that
the current evidence was insufficient to support the use of
ketamine as an adjuvant to opioids for refractory cancer pain
[76].
More recently, two multicentre double-blind RCTs found
no benefit for the addition of ketamine to opioids in treating
cancer pain. The effect of parenteral ketamine as an adjuvant
analgesic was studies in 185 adult patients with refractory pain
due to cancer or its treatment. Ketamine did not result in any
improvement in pain over placebo and was associated with
significantly more adverse events [4]. The other RCT, performed in a smaller number of patients, compared analgesic
outcome after intravenous morphine with or without a continuous intravenous infusion of ketamine. The addition of ketamine failed to provide any advantage over morphine alone
[77].
Soto et al. reviewed randomised and non-randomised clinical data on the use of oral ketamine in cancer and neuropathic
pain and found mixed results on the safety and efficacy of oral
ketamine in these settings [78]. A recent systematic review
evaluated clinical data on the use of ketamine for cancer pain.
Five RCTs and six uncontrolled studies in adult cancer patients were included. The findings in relation to effectiveness
were contradictory [79].
Overall, clinical opinion remains divided regarding ketamine as adjuvant analgesic in refractory cancer pain. Robust
evidence to support its benefit in this setting is lacking.
Cannabinoids
According to one systematic review, the existing data from
several RCTs suggest that cannabinoids are safe and effective
in controlling different types of chronic pain, particularly neuropathic pain [80]. Activation of cannabinoid receptors at presynaptic sites and interaction with opioid, serotonergic and
dopaminergic signalling are thought to result in an analgesic
effect [81].
Early findings from RCTs published in the 1970s found
moderate analgesic efficacy for cannabinoids in cancer pain,
comparable to codeine, but with dose-limiting adverse effects
[82, 83]. A non-randomised prospective observational study
in patients with advanced cancer suggested that nabinol
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decreased pain scores and morphine consumption compared
to untreated patients [84].
Nabiximols (Sativex®) is an oromucosal spray containing
a 1:1 combination of tetrahydrocannabinol (THC), the principal psychoactive constituent of the cannabis plant and
cannabidiol. It is approved in some countries for the treatment
of neuropathic pain in multiple sclerosis (MS) and refractory
pain in cancer [85]. A placebo-controlled randomised trial
assessed the effect of different doses of nabiximols on
opioid-unresponsive refractory pain in 360 cancer patients.
Low and medium doses of nabiximols were well-tolerated
and improved analgesia after 5 weeks of treatment [86]. The
safety and efficacy of this combination preparation was shown
in another RCT comparing nabiximols and THC with placebo.
While pain scores in patients receiving THC were similar to
placebo, nabiximols significantly reduced pain [87]. This effect persisted with long-term use as shown by a subsequent
open-label follow-up study [88]. The primary adverse effects
at therapeutic doses are drowsiness, somnolence and dry
mouth, and there remain concerns about psychoactive effects
and potential for addiction and abuse [89]. The limited availability of cannabinoids in many countries precludes its use for
refractory pain in most situations.
Lignocaine
Lignocaine, a local anaesthetic used topically to relieve persistent focal pain, has been used as an adjunct analgesic in
neuropathic pain caused by cancer or its treatment [89]. Systemic administration of lignocaine and other antiarrhythmic
drugs (such as flecainide and mexiletine) have also been used
for the control of postoperative or cancer pain. Preclinical and
clinical findings have indicated analgesic efficacy for
lignocaine in neuropathic pain [90]. A Cochrane review concluded that current evidence endorses the safety and efficacy
of parenteral lignocaine and its oral analogues in controlling
neuropathic pain [91]. However, as very few studies reported
their outcome in cancer patients, no definite conclusion could
be made about the use of these drugs for the management of
cancer pain.
Corticosteroids
The analgesic effect of corticosteroids, particularly in inflammatory and neuropathic pain, may result from inhibition of
cytokine-mediated perception of pain [92]. A systematic review of literature found four RCTs that assessed the outcome
of corticosteroid administration in cancer patients [93]. Two of
these studies did not adequately report the pain outcome [94,
95]; one study showed significant improvement in analgesia
and a reduction of analgesic consumption while another
showed no beneficial effect for corticosteroids [96, 97]. In
another RCT, the addition of epidural dexamethasone
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enhanced the analgesic efficacy of epidural methadone and
lidocaine with lower consumption of morphine by cancer patients with refractory pain [32]. In a more recent study, cancer
patients on opioids were randomised to methylprednisolone or
placebo. Methylprednisolone did not provide additional analgesia but improved fatigue and appetite [98]. Considering the
limited evidence on efficacy in controlling cancer pain and the
potential for serious toxicity with long-term use, a careful riskbenefit analysis should be undertaken before using corticosteroids for cancer pain.
Support Care Cancer (2015) 23:1473–1481
pain transmission. This approach aims to minimise individual
drug doses and target multiple receptors [100].
Influence of pain duration
Some studies [101] have suggested that the longer a patient
experiences pain, the harder it is to achieve adequate analgesia. This may be related to the development of drug tolerance
or drug dependence. Future studies need to determine how
important timing of pain relief is as a predictive factor and
emphasises the need for early pain control.
Discussion
The management of refractory cancer pain remains a challenge. Current strategies often involve the addition of a succession of unproven medications or interventions to standard
opioids and co-analgesics. Each additional medication has a
reduced likelihood of controlling pain and an increased potential for added toxicity [3]. As demonstrated in this review,
there is a paucity of high level evidence to guide refractory
cancer pain management. Clinicians are largely reliant on evidence extrapolated from non-cancer pain scenarios, anecdotes or uncontrolled and low-quality studies. Unproven interventions should only be considered in the context of a clinical trial or be subject to rigorous prospective evaluation using
standardised tools and data collection systems. The focus of
future pain management should be on new approaches and
optimising the use of currently available drugs and techniques
as illustrated below.
Targeted opioid therapy
Opioids remain the only analgesics with proven benefit in
severe pain. Rather than the current practice of slow dose
titration of one drug until effect or toxicity in all patients, the
emphasis should be towards ‘personalised medicine’ or
targeted therapy. Very little is known about the
pharmacokinetics/pharmacodynamics of opioids in patients
with cancer. The challenge is to determine which opioids are
best suited to each individual. This will require further research into what factors determine the pharmacokinetic profile
of opioids in individual patients [99]. Genomics may play a
role, but to date, genetic variation has not been shown to have
major effect on response to opioid therapy.
Multimodal analgesia
Rather than relying solely on opioids for all painful conditions, a combination of medications that work at different sites
or mechanisms of pain should be considered. Opioids can be
combined with anti-inflammatory medications, co-analgesics
and/or agents working through other receptors involved in
A goal-orientated approach rather than a number/score-based
approach to pain management
To date, a response to pain has been measured numerically. It
is generally considered that a 2-point improvement on an 11point numerical rating scale constitutes a clinically relevant
improvement in pain [102]. Improving or maintaining an individual’s function and their achievement of daily goals may
be more important.
Increasing use of support services and the inter-disciplinary
team
Individualised inter-disciplinary palliative care is believed to
improve patient outcomes in cancer and end-of-life patients
[103]. Anecdotally, the ability of a patient or carer in distress
to be able to contact a health professional to discuss an issue or
problem can contribute significantly to symptom relief. Several studies have shown the benefit of telephone support
[104]. Similarly, the involvement of an inter-disciplinary team
to provide holistic care may be the most effective means of
treating ‘total pain’ [105].
The development of standard definitions
The lack of international consensus for the classification and
assessment of pain for both research and clinical practice is
acknowledged and may contribute to failures in pain management [106]. A generally accepted definition of refractory pain
is essential when assessing future treatment modalities.
Acknowledgment The authors wish to thank A/Prof John Hooper and
Prof CR Pinkerton for their advice and help in this project.
Funding BA was supported from a grant from the Mater Research
Institute.
Disclosures JH sits on the medical advisory boards of Mundipharma
Pty Ltd and Menarini Australia Pty Ltd. She has contributed to the opioid
educational modules of Mundipharma Pty Ltd.
Support Care Cancer (2015) 23:1473–1481
References
1. Zech DF, Grond S, Lynch J, Hertel D, Lehmann KA (1995)
Validation of World Health Organization Guidelines for cancer pain
relief: a 10-year prospective study. Pain 63(1): 65–76
2. Mishra S, Bhatnagar S, Gupta D, Nirwani Goyal G, Jain R,
Chauhan H (2008) Management of neuropathic cancer pain following WHO analgesic ladder: a prospective study. Am J Hosp Palliat
Care 25(6):447–51
3. Currow DC, Spruyt O, Hardy J (2012) Defining refractory pain in
cancer for clinicians and researchers. J Palliat Med 15(1):5–6
4. Hardy J, Quinn S, Fazekas B, Plummer J, Eckermann S, Agar M
et al (2012) Double-blind, placebo-controlled study to assess the
efficacy and toxicity of subcutaneous ketamine in the management
of cancer pain. J Clin Oncol 30(29):3611–7
5. Fainsinger RL, Nekolaichuk CL (2008) A "TNM" classification
system for cancer pain: the Edmonton Classification System for
Cancer Pain (ECS-CP). Support Care Cancer 16(6):547–55
6. Hardy JR, Spruyt O, Quinn SJ, Devilee LR, Currow DC (2014)
Implementing practice change in chronic cancer pain management—clinician response to a phase III study of ketamine. J Intern
Med 44(6):586–91
7. Mercadante S (2014) Managing difficult pain conditions in the cancer patient. Curr Pain Headache Rep 18(2):395
8. Wiffen PJ, Wee B, Moore RA (2013) Oral morphine for cancer pain.
Cochrane Database Syst Rev 7:Cd003868
9. Zeppetella G, Davies AN (2013) Opioids for the management of
breakthrough pain in cancer patients. Cochrane Database Syst Rev
10:Cd004311
10. McNicol E (2008) Opioid side effects and their treatment in patients
with chronic cancer and noncancer pain. J Pain Palliat Care
Pharmacother 22(4):270–81
11. Faura CC, Moore RA, Horga JF, Hand CW, McQuay HJ (1996)
Morphine and morphine-6-glucuronide plasma concentrations and
effect in cancer pain. J Pain Symptom Manag 11(2):95–102
12. Klepstad P, Borchgrevink PC, Dale O, Zahlsen K, Aamo T, Fayers P
et al (2003) Routine drug monitoring of serum concentrations of
morphine, morphine-3-glucuronide and morphine-6-glucuronide
do not predict clinical observations in cancer patients. J Palliat
Med 17(8):679–87
13. Quigley C, Joel S, Patel N, Baksh A, Slevin M (2003) Plasma
concentrations of morphine, morphine-6-glucuronide and
morphine-3-glucuronide and their relationship with analgesia and
side effects in patients with cancer-related pain. J Palliat Med 17(2):
185–90
14. Radbruch L, Trottenberg P, Elsner F, Kaasa S, Caraceni A (2011)
Systematic review of the role of alternative application routes for
opioid treatment for moderate to severe cancer pain: an EPCRC
opioid guidelines project. J Palliat Med 25(5):578–96
15. Caraceni A, Hanks G, Kaasa S, Bennett MI, Brunelli C, Cherny N
et al (2012) Use of opioid analgesics in the treatment of cancer pain:
evidence-based recommendations from the EAPC. Lancet Oncol
13(2):e58–68
16. Elsner F, Radbruch L, Loick G, Gaertner J, Sabatowski R (2005)
Intravenous versus subcutaneous morphine titration in patients with
persisting exacerbation of cancer pain. J Palliat Med 8(4):743–50
17. Harris JT, Suresh KK, Rajagopal MR (2003) Intravenous morphine
for rapid control of severe cancer pain. J Palliat Med 17(3):248–56
18. Mercadante S (2007) Opioid titration in cancer pain: a critical review. Eur J Pain (London, England) 11(8):823–30
19. Hunt R, Fazekas B, Thorne D, Brooksbank M (1999) A comparison
of subcutaneous morphine and fentanyl in hospice cancer patients. J
Pain Symptom Manag 18(2):111–9
1479
20. Soares LG, Martins M, Uchoa R (2003) Intravenous fentanyl for
cancer pain: a "fast titration" protocol for the emergency room. J
Pain Symptom Manag 26(3):876–81
21. Watanabe S, Pereira J, Hanson J, Bruera E (1998) Fentanyl by
continuous subcutaneous infusion for the management of cancer
pain: a retrospective study. J Pain Symptom Manag 16(5):323–6
22. Paix A, Coleman A, Lees J, Grigson J, Brooksbank M, Thorne D
et al (1995) Subcutaneous fentanyl and sufentanil infusion substitution for morphine intolerance in cancer pain management. Pain
63(2):263–9
23. Vissers KC, Besse K, Hans G, Devulder J, Morlion B (2010) Opioid
rotation in the management of chronic pain: where is the evidence?
Pain Pract 10(2):85–93
24. Quigley C (1996) Opioid switching to improve pain relief and drug
tolerability. Cochrane Database Syst Rev (3):Cd004847
25. Dale O, Moksnes K, Kaasa S (2011) European Palliative Care
Research Collaborative pain guidelines: opioid switching to improve analgesia or reduce side effects. A systematic review. Palliat
Med 25(5):494–503
26. Ross FB, Wallis SC, Smith MT (2000) Co-administration of subantinociceptive doses of oxycodone and morphine produces marked
antinociceptive synergy with reduced CNS side-effects in rats. Pain
84(2–3):421–8
27. Park SH, Park J, Kim YS, Hong J, Cho EK, Shin DB et al (2007)
1148 POSTER Opioid rotation versus combination for cancer patients with chronic uncontrolled pain: a study. Eur J Cancer Suppl
5(4):156
28. Fallon MT, Laird BJ (2011) A systematic review of combination
step III opioid therapy in cancer pain: an EPCRC opioid guideline
project. Palliat Med 25(5):597–603
29. Bryson J, Tamber A, Seccareccia D, Zimmermann C (2006)
Methadone for treatment of cancer pain. Current Oncol Rep 8(4):
282–8
30. Bruera E, Sweeney C (2002) Methadone use in cancer patients with
pain: a review. J Palliat Med 5(1):127–38
31. Nicholson AB (2007) Methadone for cancer pain. Cochrane
Database Syst Rev 4:CD003971
32. Lauretti GR, Rizzo CC, Mattos AL, Rodrigues SW (2013) Epidural
methadone results in dose-dependent analgesia in cancer pain, further enhanced by epidural dexamethasone. Br J Cancer 108(2):259–
64
33. Cubero DI, del Giglio A (2010) Early switching from morphine to
methadone is not improved by acetaminophen in the analgesia of
oncologic patients: a prospective, double-blind, placebo-controlled
study. Support Care Cancer 18(2):235–42
34. Leppert W (2009) The role of methadone in opioid rotation—a
Polish experience. Support Care Cancer 17(5):607–12
35. Mercadante S, Ferrera P, Villari P, Adile C, Casuccio A (2012)
Switching from oxycodone to methadone in advanced cancer patients. Support Care Cancer 20(1):191–4
36. Berland DW, Malinoff HL, Weiner MA, Przybylski R (2013) When
opioids fail in chronic pain management: the role for buprenorphine
and hospitalization. Am J Ther 20(4):316–21
37. Sittl R (2006) Transdermal buprenorphine in cancer pain and palliative care. Palliat Med 20(Suppl 1):s25–30
38. Wolff RF, Aune D, Truyers C, Hernandez AV, Misso K, Riemsma R
et al (2012) Systematic review of efficacy and safety of
buprenorphine versus fentanyl or morphine in patients with chronic
moderate to severe pain. Curr Med Res Opin 28(5):833–45
39. Sittl R, Griessinger N, Likar R (2003) Analgesic efficacy and tolerability of transdermal buprenorphine in patients with inadequately
controlled chronic pain related to cancer and other disorders: a multicenter, double-blind, placebo-controlled trial. Clin Ther 25(1):
150–68
1480
40. Sorge J, Sittl R (2004) Transdermal buprenorphine in the treatment
of chronic pain: Results of a phase III, multicenter, double-blind,
placebo-controlled study. Clin Ther 26(11):1808–20
41. Poulain P, Denier W, Douma J, Hoerauf K, Samija M, Sopata M
et al (2008) Efficacy and safety of transdermal buprenorphine: a,
placebo-controlled trial in 289 patients with severe cancer pain. J
Pain Symptom Manag 36(2):117–25
42. Griessinger N, Sittl R, Likar R (2005) Transdermal buprenorphine
in clinical practice—a post-marketing surveillance study in 13,179
patients. Curr Med Res Opin 21(8):1147–56
43. Pace MC, Passavanti MB, Grella E, Mazzariello L, Maisto M,
Barbarisi M et al (2007) Buprenorphine in long-term control of
chronic pain in cancer patients. Front Biosci 12:1291–9
44. Pergolizzi JV Jr, Mercadante S, Echaburu AV, Van den Eynden B,
Fragoso RM, Mordarski S et al (2009) The role of transdermal
buprenorphine in the treatment of cancer pain: an expert panel consensus. Curr Med Res Opin 25(6):1517–28
45. Deandrea S, Corli O, Moschetti I, Apolone G (2009) Managing
severe cancer pain: the role of transdermal buprenorphine: a systematic review. Ther Clin Risk Manag 5(1):707–18
46. Tassinari D, Maltoni M (2010) Systematic review on the role of
transdermal BUPRENORPHINE (TB) for moderate to severe cancer pain: an EPCRC opioid guidelines project. Palliat Med 24(4):
S120
47. World Health Organization (1996) Cancer Pain Relief. 2nd ed.
Geneva, Switzerland
48. Nabal M, Librada S, Redondo MJ, Pigni A, Brunelli C, Caraceni A
(2012) The role of paracetamol and nonsteroidal anti-inflammatory
drugs in addition to WHO Step III opioids in the control of pain in
advanced cancer—a systematic review of the literature. Palliat Med
26(4):305–12
49. Franceschi F, Iacomini P, Marsiliani D, Cordischi C, Antonini EF,
Alesi A et al (2013) Safety and efficacy of the combination
acetaminophen-codeine in the treatment of pain of different origin.
Eur Rev Med Pharmacol Sci 17(16):2129–35
50. McNicol E, Strassels SA, Goudas L, Lau J, Carr DB (2005) NSAI
DS or paracetamol, alone or combined with opioids, for cancer pain.
Cochrane Database Syst Rev 1:CD005180
51. Mercadante S, Fulfaro F, Casuccio A (2002) A controlled study on
the use of anti-inflammatory drugs in patients with cancer pain on
m o r p h i n e t h e r ap y : e ffe c t s o n d o s e - e s c a l a t i o n a n d a
pharmacoeconomic analysis. Eur J Cancer 38(10):1358–63
52. Duarte Souza JF, Lajolo PP, Pinczowski H, del Giglio A (2007)
Adjunct dipyrone in association with oral morphine for cancerrelated pain: the sooner the better. Support Care Cancer 15(11):
1319–23
53. Verdu B, Decosterd I, Buclin T, Stiefel F, Berney A (2008)
Antidepressants for the treatment of chronic pain. Drugs 68(18):
2611–32
54. Saarto T, Wiffen PJ (2007) Antidepressants for neuropathic pain.
Cochrane Database Syst Rev 4:CD005454
55. Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ (2012)
Amitriptyline for neuropathic pain and fibromyalgia in adults.
Cochrane Database Syst Rev 12:Cd008242
56. Kajdasz DK, Iyengar S, Desaiah D, Backonja MM, Farrar JT,
Fishbain DA et al (2007) Duloxetine for the management of diabetic
peripheral neuropathic pain: evidence-based findings from post hoc
analysis of three multicenter, double-blind, placebo-controlled,
parallel-group studies. Clin Ther 29(Suppl):2536–46
57. Reuben SS, Makari-Judson G, Lurie SD (2004) Evaluation of efficacy of the perioperative administration of venlafaxine XR in the
prevention of postmastectomy pain syndrome. J Pain Symptom
Manag 27(2):133–9
58. Tasmuth T, Hartel B, Kalso E (2002) Venlafaxine in neuropathic
pain following treatment of breast cancer. Eur J Pain 6(1):17–24
Support Care Cancer (2015) 23:1473–1481
59. Kalso E, Tasmuth T, Neuvonen PJ (1996) Amitriptyline effectively
relieves neuropathic pain following treatment of breast cancer. Pain
64(2):293–302
60. Mercadante S, Arcuri E, Tirelli W, Villari P, Casuccio A (2002)
Amitriptyline in neuropathic cancer pain in patients on morphine
therapy: a placebo-controlled, double-blind crossover study. Tumori
88(3):239–42
61. Nishihara M, Arai YC, Yamamoto Y, Nishida K, Arakawa M,
Ushida T et al (2013) Combinations of low-dose antidepressants
and low-dose pregabalin as useful adjuvants to opioids for intractable, painful bone metastases. Pain Physician 16(5):E547–52
62. Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles
T et al (2013) Effect of duloxetine on pain, function, and quality of
life among patients with chemotherapy-induced painful peripheral
neuropathy: a clinical trial. JAMA 309(13):1359–67
63. Jongen JLM, Huijsman ML, Jessurun J, Ogenio K, Schipper D,
Verkouteren DRC et al (2013) The evidence for pharmacologic
treatment of neuropathic cancer pain: beneficial and adverse effects.
J Pain Symptom Manag 46(4):581–90
64. Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB,
Jensen TS et al (2007) Pharmacologic management of neuropathic
pain: evidence-based recommendations. Pain 132(3):237–51
65. Sills GJ (2006) The mechanisms of action of gabapentin and
pregabalin. Curr Opin Pharmacol 6(1):108–13
66. Bennett MI (2011) Effectiveness of antiepileptic or antidepressant
drugs when added to opioids for cancer pain: systematic review.
Palliat Med 25(5):553–9
67. Banerjee M, Pal S, Bhattacharya B, Ghosh B, Mondal S, Basu J
(2013) A comparative study of efficacy and safety of gabapentin
versus amitriptyline as coanalgesics in patients receiving opioid
analgesics for neuropathic pain in malignancy. Indian J Pharmacol
45(4):334–8
68. Caraceni A, Zecca E, Bonezzi C, Arcuri E, Yaya Tur R, Maltoni M
et al (2004) Gabapentin for neuropathic cancer pain: a controlled
trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol
22(14):2909–17
69. Mishra S, Bhatnagar S, Goyal GN, Rana SP, Upadhya SP (2012) A
comparative efficacy of amitriptyline, gabapentin, and pregabalin in
neuropathic cancer pain: a prospective double-blind placebo-controlled study. Am J Hosp Palliat Care 29(3):177–82
70. Raptis E, Vadalouca A, Stavropoulou E, Argyra E, Melemeni A,
Siafaka I (2014) Pregabalin Vs Opioids for the Treatment of
Neuropathic Cancer Pain: A Prospective, Head-to-Head, OpenLabel Study. Pain Pract 14(1): 32–42
71. Bennett MI, Laird B, van Litsenburg C, Nimour M (2013) Pregabalin
for the management of neuropathic pain in adults with cancer: a systematic review of the literature. Pain Med 14(11):1681–8
72. Prommer EE (2012) Ketamine for pain: an update of uses in palliative care. J Palliat Med 15(4):474–83
73. Jackson K, Ashby M, Howell D, Petersen J, Brumley D, Good P
et al (2010) The effectiveness and adverse effects profile of "burst"
ketamine in refractory cancer pain: the VCOG PM 1–00 study. J
Palliat Care 26(3):176–83
74. Mercadante S, Arcuri E, Tirelli W, Casuccio A (2000) Analgesic
effect of intravenous ketamine in cancer patients on morphine therapy: a, controlled, double-blind, crossover, double-dose study. J
Pain Symptom Manag 20(4):246–52
75. Yang CY, Wong CS, Chang JY, Ho ST (1996) Intrathecal ketamine
reduces morphine requirements in patients with terminal cancer
pain. Can J Anaesth 43(4):379–83
76. Bell RF, Eccleston C, Kalso EA (2012) Ketamine as an adjuvant to
opioids for cancer pain. Cochrane Database Syst Rev 11:Cd003351
77. Salas S, Frasca M, Planchet-Barraud B, Burucoa B, Pascal M,
Lapiana JM et al (2012) Ketamine analgesic effect by continuous
Support Care Cancer (2015) 23:1473–1481
intravenous infusion in refractory cancer pain: considerations about
the clinical research in palliative care. J Palliat Med 15(3):287–93
78. Soto E, Stewart DR, Mannes AJ, Ruppert SL, Baker K, Zlott D et al
(2012) Oral ketamine in the palliative care setting: a review of the
literature and case report of a patient with neurofibromatosis type 1
and glomus tumor-associated complex regional pain syndrome. Am
J Hosp Palliat Care 29(4):308–17
79. Bredlau AL, Thakur R, Korones DN, Dworkin RH (2013)
Ketamine for Pain in Adults and Children with Cancer: A
Systematic Review and Synthesis of the Literature. Pain Med
14(10):1505–17
80. Lynch ME, Campbell F (2011) Cannabinoids for treatment of
chronic non-cancer pain; a systematic review of trials. Br J Clin
Pharmacol 72(5):735–44
81. Manzanares J, Julian M, Carrascosa A (2006) Role of the cannabinoid system in pain control and therapeutic implications for the
management of acute and chronic pain episodes. Curr
Neuropharmacol 4(3):239–57
82. Jochimsen PR, Lawton RL, VerSteeg K, Noyes R Jr (1978) Effect
of benzopyranoperidine, a delta-9-THC congener, on pain. Clin
Pharmacol Ther 24(2):223–7
83. Staquet M, Gantt C, Machin D (1978) Effect of a nitrogen analog of
tetrahydrocannabinol on cancer pain. Clin Pharmacol Ther 23(4):
397–401
84. Maida V, Ennis M, Irani S, Corbo M, Dolzhykov M (2008)
Adjunctive nabilone in cancer pain and symptom management: a
prospective observational study using propensity scoring. J Support
Oncol 6(3):119–24
85. Russo EB, Guy GW, Robson PJ (2007) Cannabis, pain, and sleep:
lessons from therapeutic clinical trials of Sativex, a cannabis-based
medicine. Chem Biodivers 4(8):1729–43
86. Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova
L, Weinstein S et al (2012) Nabiximols for opioid-treated cancer
patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain 13(5):438–49
87. Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED,
Potts R, Fallon MT (2010) Multicenter, double-blind, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability
of THC:CBD extract and THC extract in patients with intractable
cancer-related pain. J Pain Symptom Manag 39(2):167–79
88. Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT (2013) An
open-label extension study to investigate the long-term safety and
tolerability of THC/CBD oromucosal spray and oromucosal THC
spray in patients with terminal cancer-related pain refractory to
strong opioid analgesics. J Pain Symptom Manag 46(2):207–18
89. Fallon MT (2013) Neuropathic pain in cancer. Br J Anaesth 111(1):
105–11
90. Tremont-Lukats IW, Challapalli V, McNicol ED, Lau J, Carr DB
(2005) Systemic administration of local anesthetics to relieve neuropathic pain: a systematic review and meta-analysis. Anesth Analg
101(6):1738–49
91. Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB
(2005) Systemic administration of local anesthetic agents to relieve
neuropathic pain. Cochrane Database Syst Rev 4, CD003345
1481
92. Watanabe S, Bruera E (1994) Corticosteroids as adjuvant analgesics. J Pain Symptom Manag 9(7):442–5
93. Paulsen Ø, Aass N, Kaasa S, Dale O (2013) Do corticosteroids
provide analgesic effects in cancer patients? A systematic literature
review. J Pain Symptom Manag 46(1):96–105
94. Della Cuna GR, Pellegrini A, Piazzi M (1989) Effect of methylprednisolone sodium succinate on quality of life in preterminal cancer
patients: a placebo-controlled, multicenter study. The
Methylprednisolone Preterminal Cancer Study Group. Eur J
Cancer Clin Oncol 25(12):1817–21
95. Popiela T, Lucchi R, Giongo F (1989) Methylprednisolone as palliative therapy for female terminal cancer patients. The
Methylprednisolone Female Preterminal Cancer Study Group. Eur
J Cancer Clin Oncol 25(12):1823–9
96. Bruera E, Roca E, Cedaro L, Carraro S, Chacon R (1985) Action of
oral methylprednisolone in terminal cancer patients: a prospective
randomized double-blind study. Cancer Treat Rep 69(7–8):751–4
97. Bruera E, Moyano JR, Sala R, Rico MA, Bosnjak S, Bertolino M
et al (2004) Dexamethasone in addition to metoclopramide for
chronic nausea in patients with advanced cancer: a controlled trial.
J Pain Symptom Manag 28(4):381–8
98. Paulsen O, Klepstad P, Rosland JH, Aass N, Albert E, Fayers P, et al.
(2014) Efficacy of Methylprednisolone on Pain, Fatigue, and
Appetite Loss in Patients With Advanced Cancer Using Opioids:
A, Placebo-Controlled, Double-Blind Trial. J Clin Oncol 32(29):
3221–8
99. Barratt DT, Bandak B, Klepstad P, Dale O, Kaasa S, Christrup LL
et al (2014) Genetic, pathological and physiological determinants of
transdermal fentanyl pharmacokinetics in 620 cancer patients of the
EPOS study. Pharmacogenet Genomics 24(4):185–94
100. Ashby MA, Fleming BG, Brooksbank M, Rounsefell B, Runciman
WB, Jackson K et al (1992) Description of a mechanistic approach
to pain management in advanced cancer. Preliminary report. Pain
51(2):153–61
101. Good P, Tullio F, Jackson K, Goodchild C, Ashby M (2005)
Prospective audit of short-term concurrent ketamine, opioid and
anti-inflammatory ('triple-agent') therapy for episodes of acute on
chronic pain. Intern Med J 35(1):39–44
102. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM (2001)
Clinical importance of changes in chronic pain intensity measured
on an 11-point numerical pain rating scale. Pain 94(2):149–58
103. Glare PA (2013) Early implementation of palliative care can improve patient outcomes. J Natl Compr Canc Netw 11(Suppl 1):
S3–9
104. Mercadante S, Giardina P (2013) Can a phone call be more effective
than an intrathecal implanted pump? Support Care Cancer 21(5):
1213–5
105. Reddy A, Hui D, Bruera E (2012) A successful palliative care intervention for cancer pain refractory to intrathecal analgesia. J Pain
Symptom Manag 44(1):124–30
106. Kaasa S, Apolone G, Klepstad P, Havard Loge J et al (2011) Expert
conference on cancer pain assessment and classification—the need
for international consensus: working proposals on international
standards. BMJ Support Palliat Care 1(3):281–287