Palliative Medicine

Evidence-based medicine (EBM) has, over the past 20 years, made us all more critical in our thinking about the efficacy and safety of interventions. This is evident in the higher standards of our spoken and written work, formal and informal, and in our approach to the subject. The downside has been the coincidence of the squeeze on healthcare funding with the emergence of the EBM ideas – it has been all too easy to misuse the tools of EBM to deny patients access to treatment, and this, together with the off-putting political correctness of the EBM approach in some quarters, has made clinicians uneasy.

Clinicians have to make decisions about therapy for the individual patient. Ideally this is guided by the best available evidence and their experience. EBM can guide one as to the population efficacy and safety of a particular intervention, but as we all know few patients are average. That guidance can only be given if there is adequate evidence, and the difficulty with guidance about symptom control is often the paucity of evidence of sufficient quality to yield credible guidance. Palliative care is often a ‘complex intervention’, and here EBM struggles to untangle which components, if any, of the complex interventions are important. The trial and review methodologies for complex intervention are wanting. Tom Chalmers, a grandfather of the EBM movement, argued late in his career that the most important function of the EBM approach was to frame the research agenda. This we think is correct. The process of systematic review of a topic throws up the deficits in trial methods and the lacunae in the data, and this then can show the way forward.

There are currently two indicators, Morphine Consumption Data and the Pain Management Index, that have been widely used to assess the efficacy of cancer pain treatment. Both are based on the World Health Organization guidelines for cancer pain and both have limitations in their ability to assess the quality of pain care for cancer patients. The published studies that have used these methods all report that cancer pain is generally undertreated in a wide range of clinical settings and care models.

The aim of this systematic review was to evaluate the evidence that oral morphine can be recommended as the first choice opioid in the treatment of moderate to severe cancer pain in updating the European Association for Palliative Care opioid recommendations. A systematic literature review was performed to update the 2007 Cochrane review ‘Oral morphine for cancer pain’. The literature search was conducted on MedLine, EMBASE and Cochrane Central Register of Controlled Trials databases. The search strategy, limited in time (from 1 July 2006 to 31 October 2009), was aimed to be as extensive as possible using both text words and MeSH/EMTREE terms; a hand search of the reference lists of identified papers was also performed. Randomized clinical trials, containing data on efficacy and/or side effects of morphine, were identified. Among the papers retrieved from the cited databases and the Cochrane review, 17 eligible studies, for a total of 2053 patients, and a meta-analysis were selected. These studies do not add significant information to the previous Cochrane review confirming the limitation of efficacy and tolerability data on opioid-naïve and non-selected populations of cancer patients treated with morphine and suggesting that oral morphine, oxycodone and hydromorphone have similar efficacy and toxicity in this patient population.

Background: To analyse the evidence supporting the widespread use of modified analgesic ladders or oral tramadol as alternatives to codeine/paracetamol for mild to moderate cancer pain.

Methods: A systematic review of the literature was independently performed by two authors. The level of evidence and risk/benefit ratio were assessed in all the selected trials. A comprehensive analysis of the level of evidence, risk/benefit ratio and strength of the recommendations was carried out. The analysis was performed using the GRADE system.

Results: Eighteen papers were included into the analysis. The level of evidence was low or very low for all the trials, and as a result the risk/benefit ratio was uncertain. Likewise, the strength of the final recommendations was considered weak negative for either the use of modified analgesic ladders (by-passing the second step of the World Health Organization (WHO) analgesic ladder) or the use of oral tramadol as an alternative to codeine/paracetamol in the second step of the WHO analgesic ladder.

Conclusions: Data supporting the role of modified two-step analgesic ladders or oral tramadol as an alternative to codeine/paracetamol are insufficient to recommend their routine use in cancer patients with mild to moderate cancer pain.

The European Association for Palliative Care recommendation for starting morphine for cancer pain is dose titration with immediate release (IR) oral morphine given every 4 h with additionally doses for breakthrough pain. As part of a EU 6th framework programme to revise the guidelines we review the evidence regarding starting treatment and dose titration of opioids in adult patients with moderate to severe cancer pain. Relevant papers were identified though a systematic search in Medline for papers published until the end of 2009. We identified 15 relevant papers. Thirteen papers were descriptive papers reporting the results from starting treatment with oral morphine (six studies), starting treatment with intravenous morphine (two studies) and starting treatment with transdermal fentanyl (four studies). All treatment strategies resulted in acceptable pain control and were well tolerated. Two randomized controlled trials were identified. One study compared starting opioid treatment with intravenous morphine versus IR oral morphine and one study compared IR oral morphine versus sustained release oral morphine.

This is a systematic review examining the management of opioid-induced central side effects. It has been conducted as part of a larger European Palliative Care Research collaborative review into the use and role of opioids in cancer pain. The review process identified 26 studies that met the inclusion criteria. The overall quality of the data was low and the few recommendations that can be made are weak and require confirmatory studies.

The main central side effects examined were sedation, cognitive failure, sleep disturbance and myoclonus. Overall there is limited evidence for the use of methylphenidate in counteracting opioid-induced sedation and cognitive disturbance. No clear recommendations can be made concerning other individual drugs for the management of any of the central side effects examined.

Given the lack of available data from this review there need to be further prospective controlled trials to confirm or refute these findings.

The objectives were to review the existing literature on management of opioid-induced nausea and vomiting in cancer patients and summarize the findings into evidence-based recommendations. Systematic searches of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were performed, using free text and MeSH/EMTREE search terms. The searches were limited to articles published in English from each database set-up date to 31 July 2009. Reference lists and relevant international conference proceedings were hand-searched. Fifty-five studies were identified, providing data on 5741 patients. The studies were classified into: (A) studies in which treatment of nausea/vomiting was the primary outcome (a total of 18 studies, of which eight studies specifically addressed opioid-induced emesis); and (B) studies in which nausea/vomiting were secondary or tertiary outcomes (37 studies). The existing evidence had several limitations, there was a lack of consistency and the overall quality was grade D. By applying the principles of the Grading of Recommendations Assessment, Development and Evaluations (GRADE) system, three weak recommendations were formulated. The current evidence is too limited to give evidence-based recommendations for the use of antiemetics for opioid-induced nausea or vomiting in cancer patients. The evidence suggests that nausea and vomiting in cancer patients receiving an opioid might be reduced by changing the opioid or opioid administration route. The evidence was also too limited to prioritize between symptomatic treatment and adjustment of the opioid treatment.

Background: Oxycodone is often used as an opioid analgesic for moderate to severe cancer-related pain, but its use varies across Europe. This systematic literature review forms the basis of guidelines for oxycodone use within the European Palliative Care Research Collaborative opioid guidelines project conducted on behalf of the European Association for Palliative Care.

Objectives: The objective of this study was to identify and assess the quality of evidence for the use of oxycodone for cancer pain in adults.

Methods: The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MedLine, EMBASE and CINAHL were systematically searched in addition to hand searching of relevant journals. Studies were included if they reported a clinical outcome relevant to the use of oxycodone in adult patients with moderate to severe cancer pain. Any form and route of oxycodone was included except intrathecal. No direct comparator was required for inclusion and studies were excluded if patients had previously switched from another strong opioid because of intolerable adverse effects or poor efficacy. This is a narrative systematic review, using the GRADE approach to assess the quality of studies and to formulate guidelines.

Results: Twenty-nine original studies were identified including a meta-analysis and 14 randomized controlled trials. The identified meta-analysis included three trials comparing oxycodone to morphine and one comparing oxycodone to hydromorphone. Four other randomized trials compared oxycodone with other opioids. The remaining randomized controlled trials compared different routes of administration or formulations of oxycodone. No additional studies that would have been suitable for addition to the meta-analysis were identified.

Conclusions: There is no evidence from the included trials of a significant difference in analgesia or adverse effects between oxycodone and morphine or hydromorphone. The evidence was graded as high quality on the basis of a well-conducted meta-analysis, with no limitations likely to affect the outcome, in addition to consistency in the results of the other studies. The research was conducted using participants relevant to cancer and palliative care populations. Oxycodone can be recommended as an alternative to morphine or hydromorphone for cancer-related pain.

The aim of this systematic review is to evaluate the scientific evidence for the efficacy and side effects of hydromorphone in the management of moderate to severe cancer pain.

Randomized and non-randomized clinical trials, reporting data on efficacy and/or side effects of hydromorphone, were identified. Thirteen eligible studies, involving 1208 patients, were selected. Seven studies compared hydromorphone with other opioids (five with morphine, one with oxycodone and one with fentanyl and buprenorphine) and five of them were randomized controlled trials (RCTs). Most of the studies were conducted on patients already receiving opioid treatment, often at stabilized doses, and most had methodological limitations. The RCTs comparing hydromorphone with morphine and oxycodone showed similar analgesic results, while the comparison of side effects showed minor differences, not consistent across studies. Due to clinical and methodological heterogeneity of the studies, a meta-analysis was not performed. In conclusion there is evidence to support the efficacy and tolerability of hydromorphone for moderate to severe cancer pain as an alternative to morphine and oxycodone, while there is no evidence to demonstrate its superiority or inferiority in comparison with morphine as the first choice opioid for the same indication.

Background: To assess the role of transdermal opioids as a front-line approach to moderate to severe cancer pain.

Methods: A systematic review of the literature was performed by two authors. An analysis of the level of evidence and risk/benefit ratio was performed for all of the selected trials. A combined analysis of the included studies to assess the level of evidence, risk/benefit ratio and strength of the recommendations was performed to determine the place of transdermal opioids in the treatment of cancer when compared with oral morphine.

Results: Thirteen papers were included in the analysis. The level of evidence was considered low for transdermal opioids (without distinction between transdermal fentanyl and transdermal buprenorphine) or transdermal fentanyl, and very low for transdermal buprenorphine. The risk/benefit ratio was considered uncertain for both transdermal opioids (fentanyl and buprenorphine) considered together and transdermal fentanyl or buprenorphine alone. The strength of the final recommendations (using the GRADE system) was weak negative for transdermal opioids (transdermal fentanyl plus transdermal buprenorphine) and transdermal fentanyl, and strong negative for transdermal buprenorphine.

Conclusions: The use of slow release oral morphine probably remains the preferred approach for these patients, with the use of transdermal opioids to be reserved for selected patients.

Aim: To address the question: is oral methadone better than placebo, or other oral/transdermal opioids in the management of cancer pain?

Method: A literature search was performed to identify relevant studies. Search strategies included: (1) methadone (title) AND placebo (title or abstract) AND pain (title or abstract); (2) methadone (title) AND randomized (title or abstract) AND pain (title or abstract) AND cancer (title or abstract). Papers were reviewed for relevance to first-line opioid therapy.

Results: No studies were identified comparing methadone to placebo for cancer pain. A single study compared methadone to placebo for neuropathic pain and demonstrated evidence of analgesic effect at a dose of 20 mg/day but not at a dose of 10 mg/day.

Four studies compared oral methadone to either oral morphine, or oral morphine and transdermal fentanyl in a first-line setting: Gourlay 1986 (N = 18), Ventafridda 1986 (N = 54), Bruera 2004 (N = 106) and Mercadante 2008 (N = 108). All studies demonstrated comparable, but not superior, analgesia with, overall, a comparable adverse effect profile. The duration of the study period for the three largest studies was 28 days. Two of these studies, Ventafridda 1986 and Mercadante 2008, indicated that, over time, the opioid escalation index was lower for methadone than for morphine. One study that used a 2:1 dose ratio between morphine and methadone was associated with a high attrition rate in the first week because of excessive sedation. This effect was not seen in the study that used a 4:1 morphine to methadone dose ratio with dose titration.

Conclusion: This limited data suggests that (1) methadone may be an equally effective candidate for first-line opioid therapy, (2) that it is possibly less expensive, (3) that there may be a propensity to sedation and dose accumulation unless there is close monitoring and conservative dose selection and (4) that it should be initiated with a calculated dose based on a morphine to methadone dose ratio of not less than 4:1.

According to a Cochrane review on opioid switching, sound evidence on the practice of substituting one strong opioid with another to improve pain control and reduce adverse effects was lacking in 2004. A systematic search strategy was developed to include studies after 2004, with adult cancer patients switching between strong opioids and reporting estimates of effect on pain and adverse effects. The search retrieved 288 publications (71 duplicates); 187 abstracts and 19 full papers were excluded. Eleven papers met the inclusion criteria; none were randomized controlled trials/meta-analyses. Studies comprised 280 patients (group size 10–32). A variety of opioids and switching strategies were studied. Pain intensity was significantly reduced in the majority of studies. Serious adverse effects were improved. Due to serious design limitations, the level of evidence was low (D). Randomized trials, with standardization of cohort classification, use of outcomes and analysis are warranted to establish the practice of opioid switching.

In this paper we describe the results of a systematic search of the literature on conversion ratios during opioid switching. This is part of a project of the European Palliative Care Research Collaboration to update the European Association for Palliative Care recommendations for the use of opioid analgesics in the treatment of cancer pain. Studies were eligible for inclusion if they involved adult patients with chronic cancer pain, contained data on opioid conversion ratios, were prospective and were written in English. Thirty-one studies were identified and included. The majority of the studies had methodological flaws and were not designed to explore or demonstrate equianalgesic dose data. However, the data allow some recommendations to be made that could be helpful to clinicians for whom there are few reliable experimental data on which to base dosing guidelines. Switching to transdermal fentanyl (TDfe) or buprenorphine (TDbu) is an option for patients with stable, controlled pain. Reliable and consistent studies show a ratio of 100 : 1 between oral morphine (ORmo) and TDfe. A ratio of 75 : 1 between ORmo and TDbu may be appropriate, but the supporting evidence here is much less robust. Data are relatively consistent to support a conversion ratio between ORmo and oral hydromorphone (ORhy) of 5 : 1. Despite some limitations, there is evidence to support the use of an approximate conversion ratio of ORmo:oral oxycodone (ORox) of 1.5 : 1. The conversion between ORox and ORhy is estimated to be 1 : 4. When switching from different opioids to methadone the conversion ratio is highly variable, ranging from 5 : 1 to 10 : 1 and much higher in some studies. The derived ratios are influenced by several factors, including the reasons for switching and previous opioid doses. An individual treatment decision and strict monitoring is recommended for patients considered at risk.

The usual management of cancer related breakthrough pain is with supplemental doses of analgesics (commonly opioids) at a dose proportional to the total around-the-clock opioid dose. The aim of this review, undertaken as part of a European Palliative Care Research Collaborative (EPCRC) project, to update the EAPC guidelines on opioid analgesics in cancer pain was to determine the evidence for the utility of opioids in the management of breakthrough pain in patients with cancer. Randomized controlled trials of opioids used as rescue medication were identified using electronic search strategies. Outcome measures sought were reduction in pain intensity measured by an appropriate scale, adverse effects, attrition, and patient satisfaction. The date of the final search was 31 July 2009. Eight studies (790 patients) met the inclusion criteria. Most studies investigated rescue medication delivery via the buccal or nasal transmucosal routes. Intravenous morphine has been compared with the transmucosal route and the two found to be effective. The oral route has not been formally tested although found to be an inferior comparator in one study. Most studies showed no meaningful relationship between the effective dose of transmucosal opioid and the around-the-clock scheduled medication or the previous rescue medication, although one study found a fixed proportion of either intravenous morphine or transmucosal fentanyl to be efficacious.

Background: Opioid use in patients with renal impairment can lead to increased adverse effects. Opioids differ in their effect in renal impairment in both efficacy and tolerability. This systematic literature review forms the basis of guidelines for opioid use in renal impairment and cancer pain as part of the European Palliative Care Research Collaborative’s opioid guidelines project.

Objective: The objective of this study was to identify and assess the quality of evidence for the safe and effective use of opioids for the relief of cancer pain in patients with renal impairment and to produce guidelines.

Search strategy: The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MedLine, EMBASE and CINAHL were systematically searched in addition to hand searching of relevant journals.

Selection criteria: Studies were included if they reported a clinical outcome relevant to the use of selected opioids in cancer-related pain and renal impairment. The selected opioids were morphine, diamorphine, codeine, dextropropoxyphene, dihydrocodeine, oxycodone, hydromorphone, buprenorphine, tramadol, alfentanil, fentanyl, sufentanil, remifentanil, pethidine and methadone. No direct comparator was required for inclusion. Studies assessing the long-term efficacy of opioids during dialysis were excluded.

Data collection and analysis: This is a narrative systematic review and no meta-analysis was performed. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of the studies and to formulate guidelines.

Main results: Fifteen original articles were identified. Eight prospective and seven retrospective clinical studies were identified but no randomized controlled trials. No results were found for diamorphine, codeine, dihydrocodeine, buprenorphine, tramadol, dextropropoxyphene, methadone or remifentanil.

Conclusions: All of the studies identified have a significant risk of bias inherent in the study methodology and there is additional significant risk of publication bias. Overall evidence is of very low quality. The direct clinical evidence in cancer-related pain and renal impairment is insufficient to allow formulation of guidelines but is suggestive of significant differences in risk between opioids.

Recommendations: Recommendations regarding opioid use in renal impairment and cancer pain are made on the basis of pharmacokinetic data, extrapolation from non-cancer pain studies and from clinical experience. The risk of opioid use in renal impairment is stratified according to the activity of opioid metabolites, potential for accumulation and reports of successful or harmful use. Fentanyl, alfentanil and methadone are identified, with caveats, as the least likely to cause harm when used appropriately. Morphine may be associated with toxicity in patients with renal impairment. Unwanted side effects with morphine may be satisfactorily dealt with by either increasing the dosing interval or reducing the 24 hour dose or by switching to an alternative opioid.

Neuropathic pain mechanisms are present in up to 40% of patients with cancer pain. In these situations, additional or adjuvant analgesic drugs (such as antidepressants or antiepileptics) are often required to optimize pain control alongside standard opioid therapy. This systematic review aimed to determine the effectiveness of antidepressants and antiepileptics when added to opioids, compared to opioids alone, for the management of pain caused directly by cancer. Prospective clinical studies, published in English that used a before-after design or randomized or non-randomized group comparisons were identified. Data were extracted on pain intensity, pain relief and adverse events. Eight studies were eligible (five randomized controlled trials) that recruited 465 patients in total, of whom 370 (79.5%) completed the study period. A narrative analysis was performed because clinical and methodological heterogeneity prevented meta-analysis.

Included studies suggested that adjuvants improve pain control within 4–8 days when added to opioids for cancer pain; the strongest evidence supports gabapentin. However, a reduction in pain intensity of greater than 1 point on a 0–10 numerical rating scale is unlikely, but an increase in adverse events is likely. For all adjuvants, the effect size was much less than that seen in patients with non-cancer neuropathic pain. Dosing strategies that can be examined in future clinical trials are suggested.

Background: A systematic review, undertaken according to an initiative to revise European Association for Palliative Care guidelines on the use of opioids for cancer pain, which aimed to analyse analgesic efficacy and side effects of spinal opioids in adult cancer patients previously treated with systemic opioids.

Methods: Search strategy elaborated with MeSH terms and words related to cancer, palliative care, pain, spinal route and opioids. PubMed, Embase and Cochrane assessed in Nov 2009. Studies were analysed and classified according to quality of evidence and strength of recommendation.

Results: Out of 2939 abstracts, 44 articles were selected (nine randomized controlled trials (RCTs), two non-randomized cohort studies, 28 uncontrolled prospective studies, and five case series). Relief of pain and/or side effects were reported in 42 articles; however, there were few studies of high quality design (RCTs) and these studies had methodological limitations that reduced their quality of evidence to very low.

Conclusion: There are few RCTs and these are of very low quality. As a result, they provide weak recommendation for using spinal opioids in adult cancer patients. Further studies are clearly needed.

The European Palliative Care Research Collaboration is updating the EAPC recommendations on opioids in cancer pain management. A systematic literature search on Medline on the use of alternative routes for opioid application identified 242 papers, with 72 publications included in the final evaluation. Two or more alternative routes of opioid application were compared in 18 papers with a total of 674 patients. The best evidence base was available for the subcutaneous route. A comparison of subcutaneous and intravenous routes found no differences, confirming both routes as feasible, effective and safe. Efficacy and safety of the rectal route was comparable to the parenteral route. The side effect profile seemed to be very similar for the subcutaneous, intravenous, rectal or transdermal routes. Local side effects were reported for rectal application as well as for subcutaneous and transdermal administration. In conclusion, the systematic review found good evidence that subcutaneous administration of morphine or other opioids is an effective alternative for cancer patients if oral treatment is not possible. However, for a number of patients intravenous, rectal or transdermal therapy will offer a good alternative to the subcutaneous route. The review found no significant differences in efficacy or side effects between the alternative application routes.

Background: The use of combinations of opioids is a common clinical practice; however, this is not advocated by the World Health Organization (WHO) analgesic ladder. As opioid combination therapy becomes used increasingly, a review of the evidence on this practice was conducted.

Aims: To carry out a systematic review of the use of strong opioids in combination in cancer pain.

Methods: The following databases were searched electronically: Embase (1980–2010 week 2), Medline (1950–2010 week 1) and the Cochrane Database of Systematic Reviews (fourth quarter 2009). Only strong opioids as defined by the WHO ladder and full opioid agonists were examined. Only studies conducted in human, adult patients with chronic cancer pain were eligible. Studies must have contained data on efficacy and/or side effects in the key point. Appraisal was conducted using predetermined criteria set by the EAPC guideline development group. All potential papers were reviewed independently by both authors.

Results: In total 596 articles were retrieved resulting in only two eligible studies, which were rated as grade C and grade D evidence. These examined morphine in combination with oxycodone or fentanyl/methadone.

Conclusion: Only a weak recommendation can be used to support combination opioid therapy. This recommendation is also based on the caveat that the desirable effects of combination opioid therapy is outweighed by any disadvantages that this would confer. Prospective randomized trials are needed to clarify the benefits and safety of combination opioid therapy.