Support Care Cancer 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 # 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
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
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]
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
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.
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.
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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 # 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
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
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]
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
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.
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.
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