Pharmacological options for the management of refractory cancer pain-what is the evidence?
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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 fashion according to the severity of pain [1]. These guidelines
standard opioid and/or co-analgesic therapy occurs in 10– are considered the world standard for pain control. It is gen-
20 % of patients. Risk factors include young age, neuropathic erally accepted that the use of these guidelines results in the
pain type, incident pain, psychological distress, previous opi- control of pain in the majority of patients [2].
oid use, high tolerance, a history of addiction and impaired Refractory cancer pain has been defined as pain related to
cognition. The management of patients with refractory pain cancer or its treatment, of at least 3 months duration, that has
remains a challenge. Treatment options include opioid manip- not responded to standard treatment with opioids and co-
ulation (parenteral delivery, rotation, combination, methadone analgesics [3]. There is no standard definition however, and
and buprenorphine), non-opioids and co-analgesics (paracet- cancer pain that is difficult to control has been variously de-
amol, non-steroidal anti-inflammatory agents, antidepressants scribed as difficult, persistent, intractable or opioid non-
and anticonvulsants), NMDA receptor antagonists, cannabi- responsive in heterogeneous populations exposed to a range
noids, lignocaine and corticosteroids. The evidence of benefit of different medications and interventions. It has been report-
for any of these agents is weak, and each additional agent ed to occur in 10–20 % of cancer patients. [4]. The character-
increases the risk of adverse events. Evidence-based guide- istics that lead to difficult pain control are said to include
lines cannot, therefore, be developed at present. New ap- young age, neuropathic pain type, incident pain, psychologi-
proaches are recommended including targeted opioid therapy, cal distress, previous opioid use, high tolerance, a history of
multimodal analgesia, a goal-oriented approach to pain man- addiction and impaired cognition [5]. The prognosis of cancer
agement and increasing use of the multidisciplinary team and pain is reported to be worse in those with mixed pain type,
support services. high pain severity, daily opioid use and poor emotional well-
being [5]. With the goal of developing evidence-based guide-
Keywords Cancer pain . Refractory . Evidence . Analgesia lines for refractory cancer pain management, the evidence for
the treatments and interventions commonly used for refractory
cancer pain was examined.
Introduction
Methods
World Health Organisation (WHO) analgesic guidelines rec-
Strategies for the management of refractory cancer pain were
ommend a limited number of drugs titrated in a step-wise
obtained from a survey of palliative care physicians [6], from
B. Afsharimani : K. Kindl : P. Good : J. Hardy (*)
reviews of refractory cancer pain management [7] and from
Department of Palliative and Supportive Care , Mater Health personal experience of the authors and palliative care col-
Services, and Mater Research Institute, University of Queensland, leagues. Evidence for the effectiveness of each intervention
Brisbane, Australia was sought primarily from the Cochrane data base and from
e-mail: janet.hardy@mater.org.au
published systematic reviews searched via Cochrane,
P. Good EMBASE, PUBMED and the Joanna Briggs Institute. In the
St Vincent’s Private Hospital, Brisbane, Australia absence of a formal Cochrane review, systematic reviews,1474 Support Care Cancer (2015) 23:1473–1481
randomised and non-randomised controlled trials were accept- other opioids or routes of administration found subcutaneous
ed. Unless specified otherwise, all trials discussed are fentanyl to be well tolerated and effective in the management
randomised controlled trials (RCTs). The quality of included of refractory pain [21]. In a small retrospective study of cancer
studies was not formally assessed or scored. Non- patients who could not tolerate subcutaneous morphine, sub-
pharmacological interventions including interventional tech- cutaneous fentanyl infusion was used to achieve analgesia
niques, complementary therapies and psychological support with limited side effects [22].
have not been included and will be the subject of a subsequent At present, there is no evidence to support the superiority of
review. parenteral versus oral opioid administration in controlling in-
tractable cancer pain. Based on available evidence, the Euro-
pean Association of Palliative Care (EAPC) recommends the
Results use of parenteral opioid infusions in cases where oral or trans-
dermal opioids fail to provide effective analgesia [15].
Opioids
Opioid rotation
Opioids remain the only analgesics with proven benefit in
severe cancer pain [8, 9]. Opioid dose escalation in the face
Changing or switching from one opioid to another has been
of increasing pain is often limited by adverse effects. Several
reported in many uncontrolled trials and descriptive studies to
approaches have been proposed to address this including the
lead to improved pain relief and/or reduction in toxicity. Pro-
proactive and aggressive management of side effects, the use
posed mechanisms include incomplete cross-tolerance, varia-
of co-analgesics, alternative routes of administration or
tion in intrinsic opioid receptor activity, inter and intra-patient
switching to a different opioid (opioid rotation) [10].
variation in pharmacokinetics/dynamics and relative
desensitisation of opioid receptors [23].
Parenteral opioids
A Cochrane review identified multiple case studies, retro-
spective reviews and prospective uncontrolled trials all of
High serum concentrations of opioids can be achieved rapidly
which showed benefit [24]. None of the studies was of suffi-
by parenteral administration although the correlation between
cient quality to be included in a meta-analysis. A subsequent
serum opioid concentrations and analgesia is poor [11–13].
systematic review identified eleven new trials, of which the
Clinical studies have shown similar efficacy and tolerability
majority showed opioid switching to be highly effective in
for both intravenous and subcutaneous delivery [14]. Subcu-
controlling cancer pain and reducing adverse effects [25].
taneous injection is generally preferred due to ease of admin-
All of the studies were of limited quality and lacked
istration, but the intravenous route can provide faster pain
randomisation or controls.
relief [15].
Few studies have explored the possibility that refractory
cancer pain responds to a rapid and intensive analgesic inter- Opioids in combination
vention. In a small open-label RCT assessing the use of par-
enteral morphine titration for pain exacerbations, pain was Theoretically, patients with pain refractory to a single opioid
controlled in 77 % of the cases with no difference between might benefit from the addition of a second opioid, especially
the subcutaneous and intravenous routes [16]. In patients with when using drugs with different characteristics such as differ-
severe pain from advanced cancer, intravenous morphine was ent lipid solubility, routes of metabolism, degree of receptor
shown to be safe and to result in better immediate analgesia activation/antagonism or opioid receptor type affinity. Animal
than oral morphine [17]. studies have confirmed the benefit of using a combination of
The peak onset of action of morphine is seen after about different opioids in improving analgesia and reducing depen-
30 min, even when administered intravenously [18]. More dence [26]. Human studies on the benefit of combination opi-
lipophilic opioids such as fentanyl readily cross the blood oid analgesia are contradictory. A prospective clinical trial
brain barrier and provide effective analgesia more rapidly. comparing combination opioid therapy and opioid rotation
One small RCT studied the benefit of subcutaneous fentanyl in cancer patients with uncontrolled pain showed similar ben-
compared to morphine in cancer patients and found both drugs efit in pain reduction and adverse effects for both manoeuvres
to be equally efficacious [19]. An uncontrolled observational [27]. In contrast, a systematic review on the efficacy and safe-
study in patients seen in emergency rooms with severe pain ty of a combination of strong opioids in controlling cancer
showed fast opioid titration with bolus intravenous fentanyl to pain included two studies that showed better pain relief and
be safe and effective in controlling pain [20]. A retrospective lower side effects when a second opioid was added to the
analysis of cancer patients commenced on subcutaneous fen- original [28]. Unfortunately, due to methodological problems
tanyl infusions because of toxicity or uncontrolled pain from in study design, only a weak recommendation could be madeSupport Care Cancer (2015) 23:1473–1481 1475
towards the use of combination strong opioids in controlling study in patients with advanced cancer, switching to metha-
cancer pain. done from oxycodone was successful in improving pain and/
or adverse effects and distress [35].
Methadone Methadone may contribute to the management of refracto-
ry pain, but to date, there remains considerable uncertainty
Methadone is often used as a second-line agent in difficult regarding dose equivalence, how best to titrate and concern
pain, instead of, or in conjunction with, other opioids. Inhibi- over potential toxicity.
tion of NMDA receptors and monoamine reuptake plus acti-
vation of kappa and delta opioid receptors is postulated to lead
to additional analgesia and reversal of opioid tolerance. Anec- Buprenorphine
dotally, methadone has benefit in patients with predominantly
neuropathic pain [29]. Buprenorphine is a semi-synthetic partial agonist of the mu
This opioid is difficult to use because of significant inter- opioid receptor with proven efficacy in controlling chronic
patient variation in efficacy and unpredictable adverse effects. pain. In patients requiring escalating doses of opioids for pain
Dose titration is complex due to the highly variable pharma- management, buprenorphine may stabilise opioid dosing, pro-
cokinetic profile of the drug. Patients must be closely moni- vide effective pain relief and improve quality of life (QoL)
tored because of the possibility of drug accumulation and [36].
unintended overdose. Methadone is frequently used in the Transdermal buprenorphine has been shown to have a more
scenario of opioid rotation or switching. The morphine dose favourable adverse effect profile compared to pure mu ago-
equivalence of methadone is not clear. It has been suggested nists such as morphine or fentanyl [37, 38]. Buprenorphine
that the morphine-to-methadone equipotent ratio varies de- transdermal patches resulted in better analgesia compared to
pending on the prior dosage of opioids administered, and that placebo and rescue buprenorphine in 157 patients with severe
in patients on higher doses of morphine, lower doses of meth- uncontrolled pain from cancer or other disorders [39]. In 137
adone are needed to achieve the same analgesic effect [30]. patients (including 45 cancer patients) with severe chronic
A Cochrane review of methadone versus opioid compara- pain, there was a trend towards better pain relief in patients
tors included nine RCTs and 459 participants. A number of randomised to transdermal buprenorphine [40]. Compared to
different dose and titration schedules were used along with placebo (with rescue analgesia), transdermal buprenorphine
various pain scales. No superiority over morphine was shown administration resulted in lower pain intensity, less need for
nor superiority with respect to the treatment of neuropathic rescue analgesics and fewer discontinuations [41]. In an open
pain. Patients on methadone had a higher rate of withdrawal observational surveillance study in 13,179 patients with
due to adverse events [31]. chronic pain (including 3690 cancer patients), effective pain
More recently, two RCTs showed a benefit for switching to relief, good tolerability and less need for rescue therapy were
methadone. In cancer patients with refractory pain, sustained- seen in patients receiving buprenorphine patches [42].
release morphine, methadone and transdermal fentanyl were Compared to sustained-release morphine administration,
similarly effective in controlling pain, but the need for opioid transdermal buprenorphine was more effective in providing
escalation was significantly less with methadone [31]. A com- long-term pain control and improving QoL in cancer patients
bination of epidural methadone and lidocaine has been com- assessed by a randomised prospective study [43].
pared to epidural lidocaine alone in cancer patients whose pain Buprenorphine is also reported to be effective in control-
was not adequately controlled with oral morphine. The addi- ling neuropathic and breakthrough pain in cancer patients and
tion of methadone to lidocaine reduced the need for oral mor- to be an option in opioid rotation [37]. Unfortunately, three
phine consumption in a dose-dependent manner. This was systematic reviews have concluded that due to the poor quality
improved when epidural dexamethasone was added to the of evidence, a definitive conclusion cannot be made on the
regimen [32]. efficacy of this drug in moderate-to-severe cancer pain
The additive effect of acetaminophen on the analgesic ef- [44–46].
ficacy of methadone in cancer patients has been studied. Par-
ticipants were switched from a stable dose of morphine to
methadone and plus either acetaminophen or placebo. Al- Non-opioid analgesics and co-analgesics
though acetaminophen showed no advantage over placebo,
switching to methadone significantly improved pain scores, The WHO analgesic ladder supports the use of non-opioid
constipation and xerostomia [33]. Switching to methadone analgesics (paracetamol and NSAIDs) and adjuvant analge-
from other opioid analgesics was also shown to be safe and sics as monotherapy for mild cancer pain and as adjunct for
effective in a prospective uncontrolled study in 21 opioid- improving opioid analgesia in moderate-to-severe pain in can-
tolerant cancer patients [34]. In a prospective uncontrolled cer patients [47].1476 Support Care Cancer (2015) 23:1473–1481
Paracetamol and NSAIDs and amitriptyline [59] in treatment-related neuropathic pain in
cancer patients demonstrated effectiveness. In patients with
Paracetamol and/or NSAIDs are used in patients with cancer- advanced cancer, there was no improvement in pain control
related pain because of their postulated opioid-sparing effect when amitriptyline was added to an opioid analgesic regimen
[48, 49]. Although effective in mild to moderate cancer pain, [60]. In pain related to bone metastases, a combination of low-
these preparations have limited value in severe pain as dose dose antidepressants (imipramine or mirtazapine) with an an-
escalation is restricted by adverse effects. A Cochrane review ticonvulsant (pregabalin) provided better pain control com-
found 14 studies that compared the efficacy of opioids and pared to pregabalin alone [61]. There is recent evidence for
NSAIDs or paracetamol, alone or in combination, in cancer the benefit of duloxetine in chemotherapy-induced painful
pain. Nine studies showed a slight advantage, one insignifi- peripheral neuropathy [62].
cant advantage and four no advantage for combinations of A systematic review analysed 14 RCTs and 16 non-
opioids and NSAIDs/paracetamol over each drug used alone randomised studies of neuropathic cancer pain based on abso-
[50]. A more recent systematic review identified two other lute risk benefit and absolute risk harm. Overall, absolute risk
studies that showed a benefit of adding NSAIDs/paracetamol benefit of antidepressants, anticonvulsants, other adjuvant an-
to an opioid analgesic regimen in cancer patients [48]. One algesics or opioids outweighed absolute risk harm [63].
RCT assessed the outcome of adding oral ketorolac to mor- Although guidelines recommend using antidepressants for
phine treatment in patients with advanced cancer. Ketorolac neuropathic pain especially in cancer patients with mood dis-
(60 mg/day) led to better analgesia and reduced the need for orders, rigorous data are lacking to endorse the use of antide-
opioid dose escalation [51]. The introduction of dipyrone to a pressants as co-analgesics in cancer pain and current practice
morphine regimen significantly improved analgesia compared is mainly based on clinical experience.
to placebo in another small RCT [52].
In summary, NSAIDs can have an opioid-sparing effect Anticonvulsants
and might improve analgesia. However, since clinical studies
are of insufficient number or quality, they can only weakly Anticonvulsants, particularly gabapentin and pregabalin, are
support the use of NSAIDs as co-analgesics in the manage- commonly used as first-line treatment in neuropathic pain
ment of cancer pain [48]. [64]. Their effect is thought to be exerted through binding to
presynaptic calcium channels, decreasing calcium influx and
Antidepressants neurotransmitter release [65].
A systematic review that analysed five RCTs and three
Neuropathic pain accounts for about one third of refractory non-randomised studies on the benefit of combining antide-
pain associated with cancer [5]. Opioid analgesics alone often pressants or antiepileptic drugs with opioid analgesics in neu-
fail to control pain completely [7]. Historically, antidepres- ropathic cancer pain found the strongest evidence for the ef-
sants have been used as co-analgesics for the management fectiveness of gabapentin [66] although a recent RCT showed
of neuropathic pain. Any analgesic effect is independent of similar analgesic efficacy for both gabapentin and amitripty-
the psychological impact and is thought to be due to enhanced line when used as co-analgesics in this setting [67]. In a RCT
norepinephrine and serotonin-mediated descending inhibitory in cancer patients, neuropathic pain intensity was significantly
output and possibly blockade of sodium channels [53]. The lower in patients treated with pregabalin as compared to pla-
evidence of benefit in the management of pain comes largely cebo [68]. Similarly, pregabalin provided better control of
from trials of non-malignant pain. neuropathic cancer pain compared to placebo, gabapentin or
A Cochrane review of tricyclic antidepressants in all pain amitriptyline and reduced opioid consumption [69].
types suggested that the number needed to treat (NNT) for at Pregabalin also provides better pain relief and patient satisfac-
least moderate pain reduction was 3.6. The number needed to tion compared to transdermal fentanyl [70]. High quality con-
harm (NNH) for minor and major adverse events was 3.7 and trolled trials are still needed to support the safety and efficacy
22, respectively. These results are similar to those for the of these drugs in cancer patients [71].
newer antidepressants such as venlafaxine (NNT=3.1) [54].
A systematic review of amitriptyline showed evidence of ben- N-methyl-D-aspartate (NMDA) receptor antagonists
efit in some non-malignant pain scenarios but failed to find
any unbiased well-designed clinical studies to support its use Ketamine is a general anaesthetic agent that is often used at
in cancer pain, [55]. Duloxetine has been shown in three subanaesthetic doses as a co-analgesic, usually in combination
double-blind RCTs to be effective in controlling diabetic pe- with opioids, particularly in neuropathic pain [72]. It interacts
ripheral neuropathic pain [56]. with multiple receptors thought to be involved in pain percep-
Very few studies have been performed in cancer-related tion. NMDA receptor activation is thought to result in neuro-
neuropathic pain. Three small RCTs of venlafaxine [57, 58] nal hyperexcitability and the development of opioid tolerance.Support Care Cancer (2015) 23:1473–1481 1477
Ketamine has been used commonly in palliative care for the decreased pain scores and morphine consumption compared
management of refractory or difficult pain, usually in combi- to untreated patients [84].
nation with opioids [73]. There is great variation in practice Nabiximols (Sativex®) is an oromucosal spray containing
with respect to the type of pain treated with this drug, the dose, a 1:1 combination of tetrahydrocannabinol (THC), the princi-
route and frequency of delivery. pal psychoactive constituent of the cannabis plant and
A Cochrane review updated in 2012 included two RCTs cannabidiol. It is approved in some countries for the treatment
that evaluated the effectiveness of adding ketamine to opioids of neuropathic pain in multiple sclerosis (MS) and refractory
in cancer patients with refractory pain. Both studies found pain in cancer [85]. A placebo-controlled randomised trial
ketamine administered intravenously [74] or intrathecally assessed the effect of different doses of nabiximols on
[75] to be effective in improving analgesia. Pooling of data opioid-unresponsive refractory pain in 360 cancer patients.
was not possible due to the small size and clinical heteroge- Low and medium doses of nabiximols were well-tolerated
neity of the studied populations. The review concluded that and improved analgesia after 5 weeks of treatment [86]. The
the current evidence was insufficient to support the use of safety and efficacy of this combination preparation was shown
ketamine as an adjuvant to opioids for refractory cancer pain in another RCT comparing nabiximols and THC with placebo.
[76]. While pain scores in patients receiving THC were similar to
More recently, two multicentre double-blind RCTs found placebo, nabiximols significantly reduced pain [87]. This ef-
no benefit for the addition of ketamine to opioids in treating fect persisted with long-term use as shown by a subsequent
cancer pain. The effect of parenteral ketamine as an adjuvant open-label follow-up study [88]. The primary adverse effects
analgesic was studies in 185 adult patients with refractory pain at therapeutic doses are drowsiness, somnolence and dry
due to cancer or its treatment. Ketamine did not result in any mouth, and there remain concerns about psychoactive effects
improvement in pain over placebo and was associated with and potential for addiction and abuse [89]. The limited avail-
significantly more adverse events [4]. The other RCT, per- ability of cannabinoids in many countries precludes its use for
formed in a smaller number of patients, compared analgesic refractory pain in most situations.
outcome after intravenous morphine with or without a contin-
uous intravenous infusion of ketamine. The addition of keta- Lignocaine
mine failed to provide any advantage over morphine alone
[77]. Lignocaine, a local anaesthetic used topically to relieve per-
Soto et al. reviewed randomised and non-randomised clin- sistent focal pain, has been used as an adjunct analgesic in
ical data on the use of oral ketamine in cancer and neuropathic neuropathic pain caused by cancer or its treatment [89]. Sys-
pain and found mixed results on the safety and efficacy of oral temic administration of lignocaine and other antiarrhythmic
ketamine in these settings [78]. A recent systematic review drugs (such as flecainide and mexiletine) have also been used
evaluated clinical data on the use of ketamine for cancer pain. for the control of postoperative or cancer pain. Preclinical and
Five RCTs and six uncontrolled studies in adult cancer pa- clinical findings have indicated analgesic efficacy for
tients were included. The findings in relation to effectiveness lignocaine in neuropathic pain [90]. A Cochrane review con-
were contradictory [79]. cluded that current evidence endorses the safety and efficacy
Overall, clinical opinion remains divided regarding keta- of parenteral lignocaine and its oral analogues in controlling
mine as adjuvant analgesic in refractory cancer pain. Robust neuropathic pain [91]. However, as very few studies reported
evidence to support its benefit in this setting is lacking. their outcome in cancer patients, no definite conclusion could
be made about the use of these drugs for the management of
Cannabinoids cancer pain.
According to one systematic review, the existing data from Corticosteroids
several RCTs suggest that cannabinoids are safe and effective
in controlling different types of chronic pain, particularly neu- The analgesic effect of corticosteroids, particularly in inflam-
ropathic pain [80]. Activation of cannabinoid receptors at pre- matory and neuropathic pain, may result from inhibition of
synaptic sites and interaction with opioid, serotonergic and cytokine-mediated perception of pain [92]. A systematic re-
dopaminergic signalling are thought to result in an analgesic view of literature found four RCTs that assessed the outcome
effect [81]. of corticosteroid administration in cancer patients [93]. Two of
Early findings from RCTs published in the 1970s found these studies did not adequately report the pain outcome [94,
moderate analgesic efficacy for cannabinoids in cancer pain, 95]; one study showed significant improvement in analgesia
comparable to codeine, but with dose-limiting adverse effects and a reduction of analgesic consumption while another
[82, 83]. A non-randomised prospective observational study showed no beneficial effect for corticosteroids [96, 97]. In
in patients with advanced cancer suggested that nabinol another RCT, the addition of epidural dexamethasone1478 Support Care Cancer (2015) 23:1473–1481
enhanced the analgesic efficacy of epidural methadone and pain transmission. This approach aims to minimise individual
lidocaine with lower consumption of morphine by cancer pa- drug doses and target multiple receptors [100].
tients with refractory pain [32]. In a more recent study, cancer
patients on opioids were randomised to methylprednisolone or
Influence of pain duration
placebo. Methylprednisolone did not provide additional anal-
gesia but improved fatigue and appetite [98]. Considering the
Some studies [101] have suggested that the longer a patient
limited evidence on efficacy in controlling cancer pain and the
experiences pain, the harder it is to achieve adequate analge-
potential for serious toxicity with long-term use, a careful risk-
sia. This may be related to the development of drug tolerance
benefit analysis should be undertaken before using corticoste-
or drug dependence. Future studies need to determine how
roids for cancer pain.
important timing of pain relief is as a predictive factor and
emphasises the need for early pain control.
Discussion
A goal-orientated approach rather than a number/score-based
The management of refractory cancer pain remains a chal- approach to pain management
lenge. Current strategies often involve the addition of a suc-
cession of unproven medications or interventions to standard To date, a response to pain has been measured numerically. It
opioids and co-analgesics. Each additional medication has a is generally considered that a 2-point improvement on an 11-
reduced likelihood of controlling pain and an increased poten- point numerical rating scale constitutes a clinically relevant
tial for added toxicity [3]. As demonstrated in this review, improvement in pain [102]. Improving or maintaining an in-
there is a paucity of high level evidence to guide refractory dividual’s function and their achievement of daily goals may
cancer pain management. Clinicians are largely reliant on ev- be more important.
idence extrapolated from non-cancer pain scenarios, anec-
dotes or uncontrolled and low-quality studies. Unproven in-
Increasing use of support services and the inter-disciplinary
terventions should only be considered in the context of a clin-
team
ical trial or be subject to rigorous prospective evaluation using
standardised tools and data collection systems. The focus of
Individualised inter-disciplinary palliative care is believed to
future pain management should be on new approaches and
improve patient outcomes in cancer and end-of-life patients
optimising the use of currently available drugs and techniques
[103]. Anecdotally, the ability of a patient or carer in distress
as illustrated below.
to be able to contact a health professional to discuss an issue or
problem can contribute significantly to symptom relief. Sev-
Targeted opioid therapy
eral studies have shown the benefit of telephone support
[104]. Similarly, the involvement of an inter-disciplinary team
Opioids remain the only analgesics with proven benefit in
to provide holistic care may be the most effective means of
severe pain. Rather than the current practice of slow dose
treating ‘total pain’ [105].
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 The development of standard definitions
pharmacokinetics/pharmacodynamics of opioids in patients
with cancer. The challenge is to determine which opioids are The lack of international consensus for the classification and
best suited to each individual. This will require further re- assessment of pain for both research and clinical practice is
search into what factors determine the pharmacokinetic profile acknowledged and may contribute to failures in pain manage-
of opioids in individual patients [99]. Genomics may play a ment [106]. A generally accepted definition of refractory pain
role, but to date, genetic variation has not been shown to have is essential when assessing future treatment modalities.
major effect on response to opioid therapy.
Acknowledgment The authors wish to thank A/Prof John Hooper and
Multimodal analgesia Prof CR Pinkerton for their advice and help in this project.
Rather than relying solely on opioids for all painful condi- Funding BA was supported from a grant from the Mater Research
Institute.
tions, a combination of medications that work at different sites
or mechanisms of pain should be considered. Opioids can be
Disclosures JH sits on the medical advisory boards of Mundipharma
combined with anti-inflammatory medications, co-analgesics Pty Ltd and Menarini Australia Pty Ltd. She has contributed to the opioid
and/or agents working through other receptors involved in educational modules of Mundipharma Pty Ltd.Support Care Cancer (2015) 23:1473–1481 1479
References 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
1. Zech DF, Grond S, Lynch J, Hertel D, Lehmann KA (1995) 21. Watanabe S, Pereira J, Hanson J, Bruera E (1998) Fentanyl by
Validation of World Health Organization Guidelines for cancer pain continuous subcutaneous infusion for the management of cancer
relief: a 10-year prospective study. Pain 63(1): 65–76 pain: a retrospective study. J Pain Symptom Manag 16(5):323–6
2. Mishra S, Bhatnagar S, Gupta D, Nirwani Goyal G, Jain R, 22. Paix A, Coleman A, Lees J, Grigson J, Brooksbank M, Thorne D
Chauhan H (2008) Management of neuropathic cancer pain follow- et al (1995) Subcutaneous fentanyl and sufentanil infusion substitu-
ing WHO analgesic ladder: a prospective study. Am J Hosp Palliat tion for morphine intolerance in cancer pain management. Pain
Care 25(6):447–51 63(2):263–9
3. Currow DC, Spruyt O, Hardy J (2012) Defining refractory pain in 23. Vissers KC, Besse K, Hans G, Devulder J, Morlion B (2010) Opioid
cancer for clinicians and researchers. J Palliat Med 15(1):5–6 rotation in the management of chronic pain: where is the evidence?
4. Hardy J, Quinn S, Fazekas B, Plummer J, Eckermann S, Agar M Pain Pract 10(2):85–93
et al (2012) Double-blind, placebo-controlled study to assess the 24. Quigley C (1996) Opioid switching to improve pain relief and drug
efficacy and toxicity of subcutaneous ketamine in the management tolerability. Cochrane Database Syst Rev (3):Cd004847
of cancer pain. J Clin Oncol 30(29):3611–7 25. Dale O, Moksnes K, Kaasa S (2011) European Palliative Care
5. Fainsinger RL, Nekolaichuk CL (2008) A "TNM" classification Research Collaborative pain guidelines: opioid switching to im-
system for cancer pain: the Edmonton Classification System for prove analgesia or reduce side effects. A systematic review. Palliat
Cancer Pain (ECS-CP). Support Care Cancer 16(6):547–55 Med 25(5):494–503
6. Hardy JR, Spruyt O, Quinn SJ, Devilee LR, Currow DC (2014) 26. Ross FB, Wallis SC, Smith MT (2000) Co-administration of sub-
Implementing practice change in chronic cancer pain manage- antinociceptive doses of oxycodone and morphine produces marked
ment—clinician response to a phase III study of ketamine. J Intern antinociceptive synergy with reduced CNS side-effects in rats. Pain
Med 44(6):586–91 84(2–3):421–8
7. Mercadante S (2014) Managing difficult pain conditions in the can- 27. Park SH, Park J, Kim YS, Hong J, Cho EK, Shin DB et al (2007)
cer patient. Curr Pain Headache Rep 18(2):395 1148 POSTER Opioid rotation versus combination for cancer pa-
8. Wiffen PJ, Wee B, Moore RA (2013) Oral morphine for cancer pain. tients with chronic uncontrolled pain: a study. Eur J Cancer Suppl
Cochrane Database Syst Rev 7:Cd003868 5(4):156
9. Zeppetella G, Davies AN (2013) Opioids for the management of 28. Fallon MT, Laird BJ (2011) A systematic review of combination
breakthrough pain in cancer patients. Cochrane Database Syst Rev step III opioid therapy in cancer pain: an EPCRC opioid guideline
10:Cd004311 project. Palliat Med 25(5):597–603
10. McNicol E (2008) Opioid side effects and their treatment in patients 29. Bryson J, Tamber A, Seccareccia D, Zimmermann C (2006)
with chronic cancer and noncancer pain. J Pain Palliat Care Methadone for treatment of cancer pain. Current Oncol Rep 8(4):
Pharmacother 22(4):270–81 282–8
11. Faura CC, Moore RA, Horga JF, Hand CW, McQuay HJ (1996) 30. Bruera E, Sweeney C (2002) Methadone use in cancer patients with
Morphine and morphine-6-glucuronide plasma concentrations and pain: a review. J Palliat Med 5(1):127–38
effect in cancer pain. J Pain Symptom Manag 11(2):95–102 31. Nicholson AB (2007) Methadone for cancer pain. Cochrane
12. Klepstad P, Borchgrevink PC, Dale O, Zahlsen K, Aamo T, Fayers P Database Syst Rev 4:CD003971
et al (2003) Routine drug monitoring of serum concentrations of 32. Lauretti GR, Rizzo CC, Mattos AL, Rodrigues SW (2013) Epidural
morphine, morphine-3-glucuronide and morphine-6-glucuronide methadone results in dose-dependent analgesia in cancer pain, fur-
do not predict clinical observations in cancer patients. J Palliat ther enhanced by epidural dexamethasone. Br J Cancer 108(2):259–
Med 17(8):679–87 64
13. Quigley C, Joel S, Patel N, Baksh A, Slevin M (2003) Plasma 33. Cubero DI, del Giglio A (2010) Early switching from morphine to
concentrations of morphine, morphine-6-glucuronide and methadone is not improved by acetaminophen in the analgesia of
morphine-3-glucuronide and their relationship with analgesia and oncologic patients: a prospective, double-blind, placebo-controlled
side effects in patients with cancer-related pain. J Palliat Med 17(2): study. Support Care Cancer 18(2):235–42
185–90 34. Leppert W (2009) The role of methadone in opioid rotation—a
14. Radbruch L, Trottenberg P, Elsner F, Kaasa S, Caraceni A (2011) Polish experience. Support Care Cancer 17(5):607–12
Systematic review of the role of alternative application routes for 35. Mercadante S, Ferrera P, Villari P, Adile C, Casuccio A (2012)
opioid treatment for moderate to severe cancer pain: an EPCRC Switching from oxycodone to methadone in advanced cancer pa-
opioid guidelines project. J Palliat Med 25(5):578–96 tients. Support Care Cancer 20(1):191–4
15. Caraceni A, Hanks G, Kaasa S, Bennett MI, Brunelli C, Cherny N 36. Berland DW, Malinoff HL, Weiner MA, Przybylski R (2013) When
et al (2012) Use of opioid analgesics in the treatment of cancer pain: opioids fail in chronic pain management: the role for buprenorphine
evidence-based recommendations from the EAPC. Lancet Oncol and hospitalization. Am J Ther 20(4):316–21
13(2):e58–68 37. Sittl R (2006) Transdermal buprenorphine in cancer pain and palli-
16. Elsner F, Radbruch L, Loick G, Gaertner J, Sabatowski R (2005) ative care. Palliat Med 20(Suppl 1):s25–30
Intravenous versus subcutaneous morphine titration in patients with 38. Wolff RF, Aune D, Truyers C, Hernandez AV, Misso K, Riemsma R
persisting exacerbation of cancer pain. J Palliat Med 8(4):743–50 et al (2012) Systematic review of efficacy and safety of
17. Harris JT, Suresh KK, Rajagopal MR (2003) Intravenous morphine buprenorphine versus fentanyl or morphine in patients with chronic
for rapid control of severe cancer pain. J Palliat Med 17(3):248–56 moderate to severe pain. Curr Med Res Opin 28(5):833–45
18. Mercadante S (2007) Opioid titration in cancer pain: a critical re- 39. Sittl R, Griessinger N, Likar R (2003) Analgesic efficacy and toler-
view. Eur J Pain (London, England) 11(8):823–30 ability of transdermal buprenorphine in patients with inadequately
19. Hunt R, Fazekas B, Thorne D, Brooksbank M (1999) A comparison controlled chronic pain related to cancer and other disorders: a mul-
of subcutaneous morphine and fentanyl in hospice cancer patients. J ticenter, double-blind, placebo-controlled trial. Clin Ther 25(1):
Pain Symptom Manag 18(2):111–9 150–681480 Support Care Cancer (2015) 23:1473–1481
40. Sorge J, Sittl R (2004) Transdermal buprenorphine in the treatment 59. Kalso E, Tasmuth T, Neuvonen PJ (1996) Amitriptyline effectively
of chronic pain: Results of a phase III, multicenter, double-blind, relieves neuropathic pain following treatment of breast cancer. Pain
placebo-controlled study. Clin Ther 26(11):1808–20 64(2):293–302
41. Poulain P, Denier W, Douma J, Hoerauf K, Samija M, Sopata M 60. Mercadante S, Arcuri E, Tirelli W, Villari P, Casuccio A (2002)
et al (2008) Efficacy and safety of transdermal buprenorphine: a, Amitriptyline in neuropathic cancer pain in patients on morphine
placebo-controlled trial in 289 patients with severe cancer pain. J therapy: a placebo-controlled, double-blind crossover study. Tumori
Pain Symptom Manag 36(2):117–25 88(3):239–42
42. Griessinger N, Sittl R, Likar R (2005) Transdermal buprenorphine 61. Nishihara M, Arai YC, Yamamoto Y, Nishida K, Arakawa M,
in clinical practice—a post-marketing surveillance study in 13,179 Ushida T et al (2013) Combinations of low-dose antidepressants
patients. Curr Med Res Opin 21(8):1147–56 and low-dose pregabalin as useful adjuvants to opioids for intracta-
43. Pace MC, Passavanti MB, Grella E, Mazzariello L, Maisto M, ble, painful bone metastases. Pain Physician 16(5):E547–52
Barbarisi M et al (2007) Buprenorphine in long-term control of 62. Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles
chronic pain in cancer patients. Front Biosci 12:1291–9 T et al (2013) Effect of duloxetine on pain, function, and quality of
44. Pergolizzi JV Jr, Mercadante S, Echaburu AV, Van den Eynden B, life among patients with chemotherapy-induced painful peripheral
Fragoso RM, Mordarski S et al (2009) The role of transdermal neuropathy: a clinical trial. JAMA 309(13):1359–67
buprenorphine in the treatment of cancer pain: an expert panel con- 63. Jongen JLM, Huijsman ML, Jessurun J, Ogenio K, Schipper D,
sensus. Curr Med Res Opin 25(6):1517–28 Verkouteren DRC et al (2013) The evidence for pharmacologic
45. Deandrea S, Corli O, Moschetti I, Apolone G (2009) Managing treatment of neuropathic cancer pain: beneficial and adverse effects.
severe cancer pain: the role of transdermal buprenorphine: a system- J Pain Symptom Manag 46(4):581–90
atic review. Ther Clin Risk Manag 5(1):707–18 64. Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB,
46. Tassinari D, Maltoni M (2010) Systematic review on the role of Jensen TS et al (2007) Pharmacologic management of neuropathic
transdermal BUPRENORPHINE (TB) for moderate to severe can- pain: evidence-based recommendations. Pain 132(3):237–51
cer pain: an EPCRC opioid guidelines project. Palliat Med 24(4): 65. Sills GJ (2006) The mechanisms of action of gabapentin and
S120 pregabalin. Curr Opin Pharmacol 6(1):108–13
47. World Health Organization (1996) Cancer Pain Relief. 2nd ed. 66. Bennett MI (2011) Effectiveness of antiepileptic or antidepressant
Geneva, Switzerland drugs when added to opioids for cancer pain: systematic review.
48. Nabal M, Librada S, Redondo MJ, Pigni A, Brunelli C, Caraceni A Palliat Med 25(5):553–9
(2012) The role of paracetamol and nonsteroidal anti-inflammatory 67. Banerjee M, Pal S, Bhattacharya B, Ghosh B, Mondal S, Basu J
drugs in addition to WHO Step III opioids in the control of pain in (2013) A comparative study of efficacy and safety of gabapentin
advanced cancer—a systematic review of the literature. Palliat Med versus amitriptyline as coanalgesics in patients receiving opioid
26(4):305–12 analgesics for neuropathic pain in malignancy. Indian J Pharmacol
49. Franceschi F, Iacomini P, Marsiliani D, Cordischi C, Antonini EF, 45(4):334–8
Alesi A et al (2013) Safety and efficacy of the combination 68. Caraceni A, Zecca E, Bonezzi C, Arcuri E, Yaya Tur R, Maltoni M
acetaminophen-codeine in the treatment of pain of different origin. et al (2004) Gabapentin for neuropathic cancer pain: a controlled
Eur Rev Med Pharmacol Sci 17(16):2129–35 trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol
50. McNicol E, Strassels SA, Goudas L, Lau J, Carr DB (2005) NSAI 22(14):2909–17
DS or paracetamol, alone or combined with opioids, for cancer pain. 69. Mishra S, Bhatnagar S, Goyal GN, Rana SP, Upadhya SP (2012) A
Cochrane Database Syst Rev 1:CD005180 comparative efficacy of amitriptyline, gabapentin, and pregabalin in
51. Mercadante S, Fulfaro F, Casuccio A (2002) A controlled study on neuropathic cancer pain: a prospective double-blind placebo-con-
the use of anti-inflammatory drugs in patients with cancer pain on trolled study. Am J Hosp Palliat Care 29(3):177–82
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
70. Raptis E, Vadalouca A, Stavropoulou E, Argyra E, Melemeni A,
pharmacoeconomic analysis. Eur J Cancer 38(10):1358–63
Siafaka I (2014) Pregabalin Vs Opioids for the Treatment of
52. Duarte Souza JF, Lajolo PP, Pinczowski H, del Giglio A (2007) Neuropathic Cancer Pain: A Prospective, Head-to-Head, Open-
Adjunct dipyrone in association with oral morphine for cancer- Label Study. Pain Pract 14(1): 32–42
related pain: the sooner the better. Support Care Cancer 15(11):
71. Bennett MI, Laird B, van Litsenburg C, Nimour M (2013) Pregabalin
1319–23
for the management of neuropathic pain in adults with cancer: a sys-
53. Verdu B, Decosterd I, Buclin T, Stiefel F, Berney A (2008)
tematic review of the literature. Pain Med 14(11):1681–8
Antidepressants for the treatment of chronic pain. Drugs 68(18):
72. Prommer EE (2012) Ketamine for pain: an update of uses in palli-
2611–32
ative care. J Palliat Med 15(4):474–83
54. Saarto T, Wiffen PJ (2007) Antidepressants for neuropathic pain.
Cochrane Database Syst Rev 4:CD005454 73. Jackson K, Ashby M, Howell D, Petersen J, Brumley D, Good P
et al (2010) The effectiveness and adverse effects profile of "burst"
55. Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ (2012)
ketamine in refractory cancer pain: the VCOG PM 1–00 study. J
Amitriptyline for neuropathic pain and fibromyalgia in adults.
Palliat Care 26(3):176–83
Cochrane Database Syst Rev 12:Cd008242
74. Mercadante S, Arcuri E, Tirelli W, Casuccio A (2000) Analgesic
56. Kajdasz DK, Iyengar S, Desaiah D, Backonja MM, Farrar JT,
effect of intravenous ketamine in cancer patients on morphine ther-
Fishbain DA et al (2007) Duloxetine for the management of diabetic
apy: a, controlled, double-blind, crossover, double-dose study. J
peripheral neuropathic pain: evidence-based findings from post hoc
Pain Symptom Manag 20(4):246–52
analysis of three multicenter, double-blind, placebo-controlled,
parallel-group studies. Clin Ther 29(Suppl):2536–46 75. Yang CY, Wong CS, Chang JY, Ho ST (1996) Intrathecal ketamine
57. Reuben SS, Makari-Judson G, Lurie SD (2004) Evaluation of effi- reduces morphine requirements in patients with terminal cancer
cacy of the perioperative administration of venlafaxine XR in the pain. Can J Anaesth 43(4):379–83
prevention of postmastectomy pain syndrome. J Pain Symptom 76. Bell RF, Eccleston C, Kalso EA (2012) Ketamine as an adjuvant to
Manag 27(2):133–9 opioids for cancer pain. Cochrane Database Syst Rev 11:Cd003351
58. Tasmuth T, Hartel B, Kalso E (2002) Venlafaxine in neuropathic 77. Salas S, Frasca M, Planchet-Barraud B, Burucoa B, Pascal M,
pain following treatment of breast cancer. Eur J Pain 6(1):17–24 Lapiana JM et al (2012) Ketamine analgesic effect by continuousSupport Care Cancer (2015) 23:1473–1481 1481
intravenous infusion in refractory cancer pain: considerations about 92. Watanabe S, Bruera E (1994) Corticosteroids as adjuvant analge-
the clinical research in palliative care. J Palliat Med 15(3):287–93 sics. J Pain Symptom Manag 9(7):442–5
78. Soto E, Stewart DR, Mannes AJ, Ruppert SL, Baker K, Zlott D et al 93. Paulsen Ø, Aass N, Kaasa S, Dale O (2013) Do corticosteroids
(2012) Oral ketamine in the palliative care setting: a review of the provide analgesic effects in cancer patients? A systematic literature
literature and case report of a patient with neurofibromatosis type 1 review. J Pain Symptom Manag 46(1):96–105
and glomus tumor-associated complex regional pain syndrome. Am 94. Della Cuna GR, Pellegrini A, Piazzi M (1989) Effect of methylpred-
J Hosp Palliat Care 29(4):308–17 nisolone sodium succinate on quality of life in preterminal cancer
79. Bredlau AL, Thakur R, Korones DN, Dworkin RH (2013) patients: a placebo-controlled, multicenter study. The
Ketamine for Pain in Adults and Children with Cancer: A Methylprednisolone Preterminal Cancer Study Group. Eur J
Systematic Review and Synthesis of the Literature. Pain Med Cancer Clin Oncol 25(12):1817–21
14(10):1505–17 95. Popiela T, Lucchi R, Giongo F (1989) Methylprednisolone as pal-
80. Lynch ME, Campbell F (2011) Cannabinoids for treatment of liative therapy for female terminal cancer patients. The
chronic non-cancer pain; a systematic review of trials. Br J Clin Methylprednisolone Female Preterminal Cancer Study Group. Eur
Pharmacol 72(5):735–44 J Cancer Clin Oncol 25(12):1823–9
81. Manzanares J, Julian M, Carrascosa A (2006) Role of the cannabi- 96. Bruera E, Roca E, Cedaro L, Carraro S, Chacon R (1985) Action of
noid system in pain control and therapeutic implications for the oral methylprednisolone in terminal cancer patients: a prospective
management of acute and chronic pain episodes. Curr randomized double-blind study. Cancer Treat Rep 69(7–8):751–4
Neuropharmacol 4(3):239–57 97. Bruera E, Moyano JR, Sala R, Rico MA, Bosnjak S, Bertolino M
82. Jochimsen PR, Lawton RL, VerSteeg K, Noyes R Jr (1978) Effect et al (2004) Dexamethasone in addition to metoclopramide for
of benzopyranoperidine, a delta-9-THC congener, on pain. Clin chronic nausea in patients with advanced cancer: a controlled trial.
Pharmacol Ther 24(2):223–7 J Pain Symptom Manag 28(4):381–8
83. Staquet M, Gantt C, Machin D (1978) Effect of a nitrogen analog of 98. Paulsen O, Klepstad P, Rosland JH, Aass N, Albert E, Fayers P, et al.
tetrahydrocannabinol on cancer pain. Clin Pharmacol Ther 23(4): (2014) Efficacy of Methylprednisolone on Pain, Fatigue, and
397–401 Appetite Loss in Patients With Advanced Cancer Using Opioids:
84. Maida V, Ennis M, Irani S, Corbo M, Dolzhykov M (2008) A, Placebo-Controlled, Double-Blind Trial. J Clin Oncol 32(29):
Adjunctive nabilone in cancer pain and symptom management: a 3221–8
prospective observational study using propensity scoring. J Support 99. Barratt DT, Bandak B, Klepstad P, Dale O, Kaasa S, Christrup LL
Oncol 6(3):119–24 et al (2014) Genetic, pathological and physiological determinants of
85. Russo EB, Guy GW, Robson PJ (2007) Cannabis, pain, and sleep: transdermal fentanyl pharmacokinetics in 620 cancer patients of the
lessons from therapeutic clinical trials of Sativex, a cannabis-based EPOS study. Pharmacogenet Genomics 24(4):185–94
medicine. Chem Biodivers 4(8):1729–43 100. Ashby MA, Fleming BG, Brooksbank M, Rounsefell B, Runciman
86. Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova WB, Jackson K et al (1992) Description of a mechanistic approach
L, Weinstein S et al (2012) Nabiximols for opioid-treated cancer to pain management in advanced cancer. Preliminary report. Pain
patients with poorly-controlled chronic pain: a randomized, place- 51(2):153–61
bo-controlled, graded-dose trial. J Pain 13(5):438–49 101. Good P, Tullio F, Jackson K, Goodchild C, Ashby M (2005)
87. Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Prospective audit of short-term concurrent ketamine, opioid and
Potts R, Fallon MT (2010) Multicenter, double-blind, placebo-con- anti-inflammatory ('triple-agent') therapy for episodes of acute on
trolled, parallel-group study of the efficacy, safety, and tolerability chronic pain. Intern Med J 35(1):39–44
of THC:CBD extract and THC extract in patients with intractable 102. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM (2001)
cancer-related pain. J Pain Symptom Manag 39(2):167–79 Clinical importance of changes in chronic pain intensity measured
88. Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT (2013) An on an 11-point numerical pain rating scale. Pain 94(2):149–58
open-label extension study to investigate the long-term safety and 103. Glare PA (2013) Early implementation of palliative care can im-
tolerability of THC/CBD oromucosal spray and oromucosal THC prove patient outcomes. J Natl Compr Canc Netw 11(Suppl 1):
spray in patients with terminal cancer-related pain refractory to S3–9
strong opioid analgesics. J Pain Symptom Manag 46(2):207–18 104. Mercadante S, Giardina P (2013) Can a phone call be more effective
89. Fallon MT (2013) Neuropathic pain in cancer. Br J Anaesth 111(1): than an intrathecal implanted pump? Support Care Cancer 21(5):
105–11 1213–5
90. Tremont-Lukats IW, Challapalli V, McNicol ED, Lau J, Carr DB 105. Reddy A, Hui D, Bruera E (2012) A successful palliative care in-
(2005) Systemic administration of local anesthetics to relieve neu- tervention for cancer pain refractory to intrathecal analgesia. J Pain
ropathic pain: a systematic review and meta-analysis. Anesth Analg Symptom Manag 44(1):124–30
101(6):1738–49 106. Kaasa S, Apolone G, Klepstad P, Havard Loge J et al (2011) Expert
91. Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB conference on cancer pain assessment and classification—the need
(2005) Systemic administration of local anesthetic agents to relieve for international consensus: working proposals on international
neuropathic pain. Cochrane Database Syst Rev 4, CD003345 standards. BMJ Support Palliat Care 1(3):281–287You can also read
