Description of the condition
Pain from cancer can be caused by direct invasion of tumour into soft tissue or bone and is often a presenting symptom at the diagnosis of cancer. A European survey published in 2009 found that of 5000 cancer patients (including 617 community-based National Health Service (NHS) patients in the United Kingdom (UK) 72% experienced pain (77% in UK) which was of moderate to severe intensity in 90% of this group (Breivik 2009). This is consistent with a recent systematic review that demonstrated cancer pain prevalence of up to 75% in advanced disease, and that almost one in two patients are under treated (Deandrea 2008).
Description of the intervention
Oxycodone is a strong opioid analgesic indicated for the treatment of moderate to severe chronic pain, including cancer pain. It is available orally as immediate release solution and tablets (for 4- hourly dosing), and as sustained release tablets (for 12- hourly dosing). It is also available as a parenteral injection. In some countries, oxycodone is available as a compound with acetaminophen/paracetamol or ibuprofen.
How the intervention might work
Oxycodone works primarily as an agonist of mu-opioid receptors in the spinal cord and brain. It has some activity at kappa-opioid receptors (which are also involved in nociception or analgesia) though the importance of this mechanism in the overall analgesic effect of oxycodone is unclear. Despite animal studies suggesting differences in pharmacodynamics, this has not been demonstrated in clinical studies to date. Therefore, the shared mechanism of action to morphine (i.e. agonist activity at mu-opioid receptors) means that clinical benefits and adverse effects are likely to be similar. However, important differences exist in the pharmacokinetics of the two drugs (morphine undergoes second phase elimination via glucuronidation, while oxycodone undergoes extensive first phase metabolism via CYP2D6 and CYP3A4 pathways) so clinical equivalence cannot be inferred (Gudin 2012; Leppert 2010).
Why it is important to do this review
The World Health Organisation published the Method for Cancer Pain Relief (WHO analgesic ladder) in 1986 (WHO 1986) which advocates a stepwise approach to analgesia for cancer pain and revolutionised the use of oral opioids. It recommended that morphine be used first line for moderate to severe cancer pain. Observational studies have suggested that this approach results in pain control for 73% of patients (Bennett 2008) with a mean reduction in pain intensity of 65% (Ventafridda 1987).
Many patients with cancer experience moderate to severe pain that requires treatment with strong analgesics. Oxycodone and morphine are examples of strong opioids that are used for the relief of cancer pain. Strong opioids are, however, not effective for pain in all patients, nor are they well-tolerated by all patients. Recent guidance on the use of opioids in cancer pain by the European Association for Palliative Care suggests that oxycodone could be used as first line treatment of moderate to severe cancer pain as an alternative to morphine (Caraceni 2012). The aim of this review is to assess whether oxycodone is associated with better pain relief and tolerability than other analgesic options for patients with cancer pain.
This protocol has been updated from Reid 2010.
To assess the effectiveness and tolerability of oxycodone for pain in adults with cancer.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials, with parallel-group or cross-over design., comparing oxycodone (any formulation and any route of administration) with placebo or an active drug (including oxycodone) for cancer background pain. We will not examine studies on breakthrough pain.
Types of participants
Adults (aged ≥ 18 years) with cancer pain.
Types of interventions
Oxycodone (any dose, formulation and route of administration) versus oxycodone (any dose, formulation and route of administration).
Oxycodone (any dose, formulation and route of administration) versus other active drug (any dose, formulation and route of administration).
Oxycodone (any dose, formulation and route of administration) versus placebo.
Types of outcome measures
Pain intensity and pain relief.
Both of these outcomes have to be patient-reported and can be reported in any transparent manner (e.g., by using numerical or verbal rating scales). We will not consider these outcomes reported by physicians, nurses or carers. If possible, we will distinguish between nociceptive and neuropathic pain.
Side effects or adverse events (e.g., constipation, nausea, vomiting, drowsiness, confusion, respiratory depression), quality of life, and patient preference.
We will consider all of these outcomes as they are reported in the included studies.
Search methods for identification of studies
We will not apply language, date or publication status (published in full, published as abstract, unpublished) restrictions to the search.
We will identify relevant trials by searching the following databases:
- The Cochrane Central Register of Controlled Trials (CENTRAL)
- MEDLINE (OVID) (1946 to date)
- MEDLINE in process
- EMBASE (OVID) (1947 to date)
- Science Citation Index (Web of Science) (1899 to date)
- Conference Proceedings Citation Index - Science (Web of Science) (1990 to date)
- BIOSIS (Web of Science) (1926 to date)
- PsycINFO (OVID) (1806 to date)
We will apply the Cochrane highly sensitive search strategy for identifying randomised control trials to this search (Lefebvre 2011). The search strategy for MEDLINE is in Appendix 1 and will be modified for other databases using the appropriate syntax and controlled vocabulary.
Searching other resources
We will check the bibliographic references of relevant identified studies in order to find additional trials not identified by the electronic searches. We will also search Clinicaltrials.gov and metaRegister of Controlled Trials (mRCT) as complementary sources for related studies. We will contact authors of the included studies to ask if they know of any other relevant studies.
Data collection and analysis
Selection of studies
Two of the review authors (MSH, MIB) will assess the titles and abstracts of all the studies identified by the search for potential inclusion. We will independently consider the full records of all potentially relevant studies for inclusion by applying the selection criteria outlined in the Criteria for considering studies for this review section. We will resolve potential disagreements by discussion. We will not restrict the inclusion criteria by date, language or publication status (published in full, published as abstract, unpublished).
Data extraction and management
Using a standardised data extraction form, two authors (MSH, MIB) will extract data pertaining to study design, participant detail (including age, cancer characteristics, previous analgesic medication and setting), interventions (including details about titration), and outcomes. We will resolve potential disagreements by discussion. If there are studies for which only a subgroup of the participants meet the inclusion criteria for the current review, we will only extract data on this subgroup provided randomisation will not be broken.
Assessment of risk of bias in included studies
Two of the authors (MSH, MIB) will independently assess the methodological quality of each of the included studies by using the 'Risk of bias' assessment method outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). For each study we will assess the risk of bias for the following domains: Selection bias (study level; 2 items; random sequence generation, allocation concealment), performance bias (outcome level; 2 items; blinding of patients, blinding of treating personnel), detection bias (outcome level; 1 item; blinding of outcome assessment), attrition bias (outcome level; 1 item; incomplete outcome data), and reporting bias (study level; 1 item; selective reporting). We will also include an item that assesses the adequacy of titration. Each of the 'Risk of bias' items requires a 'low risk', 'high risk' or 'unclear risk' response. We will also document the reasons for each response in accordance with Higgins 2011. We will resolve potential disagreements between the 'Risk of bias' ratings through discussion.
Measures of treatment effect
For continuous outcomes we will extract the means and standard deviations and we will use these to estimate the mean difference between the treatments along with the 95% confidence interval (CI), if the outcome is measured on the same scale in the studies. Where the outcome is measured on different scales, we will report the standardised mean difference with 95% CIs instead. For dichotomous outcomes we will extract event rates and calculate risk ratios.
Unit of analysis issues
The patient will be the unit of analysis, but if the data reported in any included cross-over trials cannot be otherwise incorporated into the analyses (see Dealing with missing data), we will include them as if the design had been parallel group. Higgins 2011 (in chapter 16) points out that this approach, while giving rise to unit-of analysis error, is nevertheless conservative as it results in an under-weighting of the data. If we include cross-over trial data in this manner we will perform sensitivity analyses assessing the impact of this strategy.
Dealing with missing data
In cases where data are missing, we will contact the authors to request the missing data. Missing data imputation will be limited to the imputation of missing standard deviations if enough information is available from the studies to calculate the standard deviation according to the methods outlined by Higgins 2011. We will record the drop-out/missing data rates in the 'Risk of bias' tables under the items on attrition bias, and we will address the potential effect of the missing data on the results in sensitivity analyses and in the Discussion section of the review. In all cases we will aim to perform intention-to-treat analyses.
Assessment of heterogeneity
We will assess heterogeneity by using the I
Assessment of reporting biases
In addition to implementing the comprehensive search strategy outlined in the section Search methods for identification of studies, the risk of outcome reporting bias will be illustrated in the 'Risk of bias' summary figures that we will construct for each study and each type of assessed bias.
We will enter the data extracted from the included studies into Review Manager (RevMan 2012) which will be used for data synthesis. We will analyse continuous outcomes using the generic inverse variance method, and dichotomous outcomes using the Mantel-Haenszel method in accordance with Higgins 2011. If I
Subgroup analysis and investigation of heterogeneity
Different aspects of the trials are likely to contribute heterogeneity to the proposed main analyses. If there are sufficient data, we will therefore perform subgroup analyses based on doses, titration, formulations (e.g., immediate-release, sustained-release), routes of administration (e.g. oral, rectal), length of the trials, and populations (e.g. adults, opioid-naive patients).
If sufficient data are available, we will examine the robustness of the meta-analyses by conducting sensitivity analyses using different components of the 'Risk of bias' assessment, particularly those relating to whether allocation concealment and blinding were adequate. We will conduct further sensitivity analyses to examine the impact of missing data on the results if a large proportion of the studies are at an 'unknown' or 'high risk' of attrition bias, and finally, sensitivity analyses will examine whether publication status and trial size influence the results.
This article presents an extension to a systematic review undertaken as part of the 2011 National Institute for Health and Clinical Excellence (NICE) guideline on “Opioids in palliative care” (NICE 2012) which was developed by the National Collaborating Centre for Cancer (NCC-C). The NCC-C receives funding from NICE.
Appendix 1. MEDLINE Search Strategy
23. m oxy.tw.
40. exp Neoplasms/
41. (cancer$ or neoplas$ or tumo$ or carcinoma$ or hodgkin$ or nonhodgkin$ or adenocarcinoma$ or leuk?emia$1 or metasta$ or malignan$ or lymphoma$ or sarcoma$ or melanoma$ or myeloma$ or oncolog$).tw.
42. 40 or 41
43. 39 and 42
44. randomized controlled trial.pt.
45. controlled clinical trial.pt.
48. drug therapy.fs.
53. exp animals/ not humans.sh.
54. 52 not 53
55. 43 and 54
Protocol first published: Issue 4, 2002
Contributions of authors
MSH and MIB conceived and designed the review and wrote the protocol. MSH coordinated the review and devised the analysis strategy. SA devised the search strategy.
Declarations of interest
This protocol was originally published in Issue 4, 2002. As the authors were unable to commit time to the completion of the full review it was then withdrawn in January 2009. The original authors intended to publish in 2010 (Reid 2010), but experienced further delays. The current author team will complete the full review.