Paracetamol, NSAIDs Reduce Morphine-Related Side-Effects
Non-opioid analgesics, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase 2 (COX-2) inhibitors are often given along with morphine as part of multimodal analgesia after major surgery. We have undertaken a systematic review and a mixed treatment comparison (MTC) analysis in order to determine explicitly which class of non-opioid analgesic, paracetamol, NSAIDs, or COX-2 inhibitors is the most effective in reducing morphine consumption and morphine-related adverse effects. Sixty relevant studies were identified. The MTC found that when paracetamol, NSAIDs, or COX-2 inhibitors were added to patient-controlled analgesia (PCA) morphine, there was a statistically significant reduction in morphine consumption: paracetamol [mean difference (MD) −6.34 mg; 95% credibility interval (CrI) −9.02, −3.65], NSAIDs (MD −10.18; 95% CrI −11.65, −8.72), and COX-2 inhibitors (MD −10.92; 95% CrI −12.77, −9.08). There was a significant reduction in nausea and postoperative nausea and vomiting with NSAIDs compared with placebo (odds ratio 0.70; 95% CrI 0.53, 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared with paracetamol or COX-2 inhibitors. There was no statistically significant difference in sedation between any intervention and comparator. On the basis of six trials (n=695), 2.4% of participants receiving an NSAID experienced surgical-related bleeding compared with 0.4% with placebo. The MTC found that there is a decrease in 24 h morphine consumption when paracetamol, NSAID, or COX-2 inhibitors are given in addition to PCA morphine after surgery, with no clear difference between them. Similarly, the benefits in terms of reduction in morphine-related adverse effects do not strongly favour one of the three non-opioid analgesics.
Multimodal analgesia, where morphine is given with a non-opioid such as paracetamol, is often used to reduce morphine-related adverse effects. The underlying principle is that the different modes of action of morphine and the non-opioid drug allow optimum analgesia to be maintained with a lower dose of morphine and consequently a lower incidence of morphine-related adverse effects.
We were asked to undertake a systematic review comparing the relative effectiveness of paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), and cyclo-oxygenase 2 (COX-2) inhibitors in reducing morphine consumption after major surgery. The ideal evidence would be a systematic review of randomized controlled trials (RCTs) directly comparing the three drugs, preferably with a fourth arm for placebo. Importantly, thus far, there has been no explicit, statistically robust, comparison of the three non-opioids with one another, reflecting the paucity of direct head-to-head comparisons of the treatments. Previous systematic reviews using a standard meta-analysis compared each non-opioid with placebo. These concluded that all three reduced morphine consumption in the first 24 h after surgery, but only NSAIDs appear to reduce morphine-related adverse effects.
There is an increasing interest in the development of statistical methods to address situations where there is a lack of head-to-head comparisons between treatments, specifically mixed treatment comparison (MTC), also called network meta-analysis. MTC is an extension of traditional meta-analysis that uses indirect evidence (e.g. treatment effect of drug A vs drug B calculated from the treatment effect of drug A vs drug C and drug B vs drug C), and direct evidence, if available, and uses a network of all available comparisons from all the available trials. It simultaneously compares all treatments and ranks them according to their effectiveness for a given outcome. A key feature of MTC is that the randomized treatment comparison from each trial is used thereby maintaining randomization. This approach has been applied to a range of interventions including new generation antidepressants, drug-eluting and bare-metal stents, and stroke prevention treatments.
The aim of our study was to apply the technique of MTC analysis to determine explicitly which class, if any, of non-opioid analgesic (paracetamol, NSAIDs, or COX-2 inhibitor) is most effective at reducing morphine consumption and morphine-related adverse effects when used as part of multimodal analgesia after major surgery. In addition, our review provides a substantial update of the recent work on this topic, with the inclusion of 20 new trials, while excluding drugs that are no longer licensed (valdecoxib and rofecoxib) and the studies published by S.S. Reuben which have been retracted due to data falsification.
Abstract and Introduction
Abstract
Non-opioid analgesics, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase 2 (COX-2) inhibitors are often given along with morphine as part of multimodal analgesia after major surgery. We have undertaken a systematic review and a mixed treatment comparison (MTC) analysis in order to determine explicitly which class of non-opioid analgesic, paracetamol, NSAIDs, or COX-2 inhibitors is the most effective in reducing morphine consumption and morphine-related adverse effects. Sixty relevant studies were identified. The MTC found that when paracetamol, NSAIDs, or COX-2 inhibitors were added to patient-controlled analgesia (PCA) morphine, there was a statistically significant reduction in morphine consumption: paracetamol [mean difference (MD) −6.34 mg; 95% credibility interval (CrI) −9.02, −3.65], NSAIDs (MD −10.18; 95% CrI −11.65, −8.72), and COX-2 inhibitors (MD −10.92; 95% CrI −12.77, −9.08). There was a significant reduction in nausea and postoperative nausea and vomiting with NSAIDs compared with placebo (odds ratio 0.70; 95% CrI 0.53, 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared with paracetamol or COX-2 inhibitors. There was no statistically significant difference in sedation between any intervention and comparator. On the basis of six trials (n=695), 2.4% of participants receiving an NSAID experienced surgical-related bleeding compared with 0.4% with placebo. The MTC found that there is a decrease in 24 h morphine consumption when paracetamol, NSAID, or COX-2 inhibitors are given in addition to PCA morphine after surgery, with no clear difference between them. Similarly, the benefits in terms of reduction in morphine-related adverse effects do not strongly favour one of the three non-opioid analgesics.
Introduction
Multimodal analgesia, where morphine is given with a non-opioid such as paracetamol, is often used to reduce morphine-related adverse effects. The underlying principle is that the different modes of action of morphine and the non-opioid drug allow optimum analgesia to be maintained with a lower dose of morphine and consequently a lower incidence of morphine-related adverse effects.
We were asked to undertake a systematic review comparing the relative effectiveness of paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), and cyclo-oxygenase 2 (COX-2) inhibitors in reducing morphine consumption after major surgery. The ideal evidence would be a systematic review of randomized controlled trials (RCTs) directly comparing the three drugs, preferably with a fourth arm for placebo. Importantly, thus far, there has been no explicit, statistically robust, comparison of the three non-opioids with one another, reflecting the paucity of direct head-to-head comparisons of the treatments. Previous systematic reviews using a standard meta-analysis compared each non-opioid with placebo. These concluded that all three reduced morphine consumption in the first 24 h after surgery, but only NSAIDs appear to reduce morphine-related adverse effects.
There is an increasing interest in the development of statistical methods to address situations where there is a lack of head-to-head comparisons between treatments, specifically mixed treatment comparison (MTC), also called network meta-analysis. MTC is an extension of traditional meta-analysis that uses indirect evidence (e.g. treatment effect of drug A vs drug B calculated from the treatment effect of drug A vs drug C and drug B vs drug C), and direct evidence, if available, and uses a network of all available comparisons from all the available trials. It simultaneously compares all treatments and ranks them according to their effectiveness for a given outcome. A key feature of MTC is that the randomized treatment comparison from each trial is used thereby maintaining randomization. This approach has been applied to a range of interventions including new generation antidepressants, drug-eluting and bare-metal stents, and stroke prevention treatments.
The aim of our study was to apply the technique of MTC analysis to determine explicitly which class, if any, of non-opioid analgesic (paracetamol, NSAIDs, or COX-2 inhibitor) is most effective at reducing morphine consumption and morphine-related adverse effects when used as part of multimodal analgesia after major surgery. In addition, our review provides a substantial update of the recent work on this topic, with the inclusion of 20 new trials, while excluding drugs that are no longer licensed (valdecoxib and rofecoxib) and the studies published by S.S. Reuben which have been retracted due to data falsification.
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