Oxycodone for cancer‐related pain
Many people with cancer experience moderate to severe pain that requires treatment with strong opioids, such as oxycodone and morphine. Strong opioids are, however, not effective for pain in all people, neither are they well tolerated by all people. The aim of this review was to assess whether oxycodone is associated with better pain relief and tolerability than other analgesic options for adults with cancer pain. This is an updated Cochrane review previously published in 2017.
To assess the effectiveness and tolerability of oxycodone by any route of administration for pain in adults with cancer.
For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE and MEDLINE In‐Process (Ovid), Embase (Ovid), Science Citation Index, Conference Proceedings Citation Index ‐ Science (ISI Web of Science), BIOSIS (ISI), and PsycINFO (Ovid) to November 2021. We also searched four trial registries, checked the bibliographic references of relevant studies, and contacted the authors of the included studies. We applied no language, date, or publication status restrictions.
We included randomised controlled trials (parallel‐group or cross‐over) comparing oxycodone (any formulation or route of administration) with placebo or an active drug (including oxycodone) for cancer background pain in adults by examining pain intensity/relief, adverse events, quality of life, and participant preference.
Data collection and analysis
Two review authors independently sifted the search, extracted data and assessed the included studies using standard Cochrane methodology. We meta‐analysed pain intensity data using the generic inverse variance method, and pain relief and adverse events using the Mantel‐Haenszel method, or summarised these data narratively along with the quality of life and participant preference data. We assessed the overall certainty of the evidence using GRADE.
For this update, we identified 19 new studies (1836 participants) for inclusion. In total, we included 42 studies which enrolled/randomised 4485 participants, with 3945 of these analysed for efficacy and 4176 for safety. The studies examined a number of different drug comparisons.
Controlled‐release (CR; typically taken every 12 hours) oxycodone versus immediate‐release (IR; taken every 4‐6 hours) oxycodone
Pooled analysis of three of the four studies comparing CR oxycodone to IR oxycodone suggest that there is little to no difference between CR and IR oxycodone in pain intensity (standardised mean difference (SMD) 0.12, 95% confidence interval (CI) ‐0.1 to 0.34; n = 319; very low‐certainty evidence). The evidence is very uncertain about the effect on adverse events, including constipation (RR 0.71, 95% CI 0.45 to 1.13), drowsiness/somnolence (RR 1.03, 95% CI 0.69 to 1.54), nausea (RR 0.85, 95% CI 0.56 to 1.28), and vomiting (RR 0.66, 95% CI 0.38 to 1.15) (very low‐certainty evidence). There were no data available for quality of life or participant preference, however, three studies suggested that treatment acceptability may be similar between groups (low‐certainty evidence).
CR oxycodone versus CR morphine
The majority of the 24 studies comparing CR oxycodone to CR morphine reported either pain intensity (continuous variable), pain relief (dichotomous variable), or both. Pooled analysis indicated that pain intensity may be lower (better) after treatment with CR morphine than CR oxycodone (SMD 0.14, 95% CI 0.01 to 0.27; n = 882 in 7 studies; low‐certainty evidence). This SMD is equivalent to a difference of 0.27 points on the Brief Pain Inventory scale (0‐10 numerical rating scale), which is not clinically significant. Pooled analyses also suggested that there may be little to no difference in the proportion of participants achieving complete or significant pain relief (RR 1.02, 95% CI 0.95 to 1.10; n = 1249 in 13 studies; low‐certainty evidence).
The RR for constipation (RR 0.75, 95% CI 0.66 to 0.86) may be lower after treatment with CR oxycodone than after CR morphine. Pooled analyses showed that, for most of the adverse events, the CIs were wide, including no effect as well as potential benefit and harm: drowsiness/somnolence (RR 0.88, 95% CI 0.74 to 1.05), nausea (RR 0.93, 95% CI 0.77 to 1.12), and vomiting (RR 0.81, 95% CI 0.63 to 1.04) (low or very low‐certainty evidence). No data were available for quality of life. The evidence is very uncertain about the treatment effects on treatment acceptability and participant preference.
The remaining studies either compared oxycodone in various formulations or compared oxycodone to different alternative opioids. None found any clear superiority or inferiority of oxycodone for cancer pain, neither as an analgesic agent nor in terms of adverse event rates and treatment acceptability. The certainty of this evidence base was limited by the high or unclear risk of bias of the studies and by imprecision due to low or very low event rates or participant numbers for many outcomes.
The conclusions have not changed since the previous version of this review (in 2017). We found low‐certainty evidence that there may be little to no difference in pain intensity, pain relief and adverse events between oxycodone and other strong opioids including morphine, commonly considered the gold standard strong opioid. Although we identified a benefit for pain relief in favour of CR morphine over CR oxycodone, this was not clinically significant and did not persist following sensitivity analysis and so we do not consider this important. However, we found that constipation and hallucinations occurred less often with CR oxycodone than with CR morphine; but the certainty of this evidence was either very low or the finding did not persist following sensitivity analysis, so these findings should be treated with utmost caution. Our conclusions are consistent with other reviews and suggest that, while the reliability of the evidence base is low, given the absence of important differences within this analysis, it seems unlikely that larger head‐to‐head studies of oxycodone versus morphine are justified, although well‐designed trials comparing oxycodone to other strong analgesics may well be useful. For clinical purposes, oxycodone or morphine can be used as first‐line oral opioids for relief of cancer pain in adults.
Mia Schmidt-Hansen, Michael I Bennett, Stephanie Arnold, Nathan Bromham, Jennifer S Hilgart, Andrew J Page, Yuan Chi
Plain language summary
Oxycodone for cancer‐related pain in adults
Many people with cancer experience moderate to severe pain that requires treatment with strong painkillers that are classified as opioids.
Oxycodone and morphine are examples of these opioids that are used for the relief of cancer pain. However, strong painkillers are not effective for pain in all people, neither are they well tolerated by all people. The aim of this review was to assess whether oxycodone is associated with better pain relief and fewer side effects than other strong painkillers for adults with cancer pain.
For this update, in November 2021, we found 19 additional relevant studies. In total, we included 42 studies with 4485 participants. These studies compared the painkilling ability (benefit) and side effects (harms) of different types of oxycodone to each other or to other strong painkillers.
In general, the studies showed no difference between oxycodone taken every 4‐6 (immediate‐release) or every 12 (controlled‐release) hours. In general, the studies also showed no difference between oxycodone and other strong pain killers such as morphine.
All the strong painkillers examined in the studies also have a number of unwanted effects, such as vomiting, constipation, and drowsiness. Overall, these do not differ between oxycodone and the other strong painkillers. Hallucinations (where people experience imaginary things, e.g. hearing voices) are much less common as a side effect of strong painkillers, and we found that they were less likely with oxycodone than with morphine.
Overall, we found that the current evidence is comprised of studies that contained small numbers of people, of which many (12.2%) did not finish the studies. However, since there was very little difference between oxycodone and morphine, more research in this area is unlikely to be undertaken. This is partly because recruitment and retention of participants in this context is challenging. Studies looking at oxycodone compared to other strong painkillers may be useful.
Certainty of the evidence
We rated the certainty of the evidence from studies using four levels: very low, low, moderate, or high. Very low‐certainty evidence means that we are very uncertain about the results. High‐certainty evidence means that we are very confident in the results. Overall, the certainty of the evidence in this review was rated low or very low, meaning that we are not sure about the results because of problems with study quality and small size.
Mia Schmidt-Hansen, Michael I Bennett, Stephanie Arnold, Nathan Bromham, Jennifer S Hilgart, Andrew J Page, Yuan Chi
Implications for practice
Since the last version of this review, none of the new relevant studies have provided additional information to change the conclusions.
For adults with cancer pain
We found low‐certainty evidence that there may be little to no difference between oxycodone and other strong opioids in pain intensity, pain relief and adverse events for adults with cancer. Although we identified a clinically insignificant benefit on pain relief in favour of controlled‐release (CR) morphine compared to CR oxycodone, this did not persist following sensitivity analysis excluding cross‐over trials and so we do not consider this important. We did find that the frequency of hallucinations may be increased after treatment with CR morphine (7.8%) compared to CR oxycodone (4%).
We found low‐certainty evidence that there may be little to no difference in pain intensity, cancer pain relief and adverse events between oxycodone and other strong opioids including morphine, which is commonly considered the gold standard strong opioid. Although we identified a clinically insignificant benefit on pain relief in favour of CR morphine compared to CR oxycodone, this did not persist following sensitivity analysis and so we do not consider this important. We found that the risk of hallucinations may be increased with CR morphine but we also found a numerically higher frequency of myoclonus (another excitatory opioid adverse effect) with CR oxycodone and we did not find any differences in reported drowsiness or confusion. The interpretation of increased relative risk of hallucinations should therefore be treated with caution given the low certainty of evidence. We also found low‐certainty evidence that there may be little to no difference in pain intensity, cancer pain relief and adverse events between CR and IR oxycodone, which suggests there is no benefit of OR over IR oxycodone. However, evidence on patient preference was lacking in these studies.
For policy makers
The findings of this review are consistent with current international guidance on using oxycodone or morphine as first‐line opioids for adults with cancer‐related pain.
For funders of the intervention
We did not undertake cost‐effectiveness analysis.
Implications for research
We found that the current evidence base is comprised of studies that contained small numbers of participants in which there was a significant (> 12%) dropout rate. For example, the direct comparison meta‐analysis between CR oxycodone and CR morphine was based on fewer than 450 cancer participants in each treatment group; this was a very small evidence base. However, given the absence of important differences within this analysis, it seems unlikely that larger head‐to‐head studies of oxycodone versus morphine will be undertaken. In part, this is because recruitment and retention of participants is challenging in this context. Well‐designed randomised controlled trials comparing oxycodone to other strong analgesics may well be useful.
Future randomised controlled trials assessing the effectiveness and tolerability of oxycodone for pain in adults with cancer need to be adequately powered, well‐designed, protocol‐driven and fully reported following the most up‐to‐date CONSORT (Schulz 2010) trial reporting guidelines, including adequate reporting of participant baseline characteristics and co‐interventions.
For future cancer pain studies, developing a single outcome that combines good pain control (no more than mild on a verbal rating scale) with acceptable adverse effects (perhaps no more than mild severity on any adverse event) would enable a clearer comparison between any analgesics used in this context.