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NIHR Health Technology Assessment programme: Executive Summaries. Southampton (UK): NIHR Journals Library; 2003-.

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NIHR Health Technology Assessment programme: Executive Summaries.

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Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review

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Patient-controlled analgesia (PCA) is a mainstay in the control of pain after major surgery. The drug most commonly used with PCA is morphine, but its administration can result in adverse effects, most commonly nausea and vomiting. Paracetamol (acetaminophen), non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase 2 (COX-2) inhibitors are commonly used in conjunction with morphine following major surgery with the aim of reducing morphine consumption and the associated adverse effects. These non-opioids also have their own adverse effects. NSAIDs are associated with prolonged bleeding time and adverse gastrointestinal effects amongst other outcomes. The use of COX-2 inhibitors has been associated with increased thromboembolic events such as myocardial infarction and stroke, although these associations tend to be seen only with long-term use.


To determine which class of non-opioid analgesics – paracetamol, NSAIDs or COX-2 inhibitors – is the most effective at reducing morphine consumption and associated adverse effects when used as part of multimodal analgesia following major surgery.


We conducted a systematic review of the effectiveness literature, which updated a previous review on this topic. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for the period January 2003 to February 2009. Published and unpublished studies were eligible and no language restrictions were applied. The reference lists of relevant systematic reviews were checked to identify relevant studies.

Two researchers independently screened studies for relevance based on the inclusion criteria, and disagreements were resolved by consensus or through discussion with a third member of the team. Randomised controlled trials comparing paracetamol, NSAIDs or COX-2 inhibitors to each other or placebo, in adults receiving PCA morphine following major surgery, were included. The COX-2 inhibitors rofecoxib and valdecoxib were excluded as these are no longer licensed in the UK. Only trials that reported 24-hour morphine consumption were included. The other outcomes of interest were morphine-related adverse effects (respiratory depression, nausea, vomiting, urinary retention, pruritus, dizziness and sedation) and adverse effects related to the non-opioids. The inclusion criteria differed slightly from the earlier review and the trials from this earlier review were screened for inclusion in the update.

Data were extracted by one researcher into a standardised form and checked by a second. A standardised scale was used to assess whether randomisation, concealment of allocation, double blinding, and the flow of patients within the trial were adequately described or not.

The main analysis was a mixed treatment comparison (MTC) evaluating the relative effects of the four treatment classes: paracetamol, NSAIDs, COX-2 inhibitors and placebo. Four main outcomes were prioritised for the analysis. These were 24-hour morphine consumption, sedation, nausea and vomiting, and surgical bleeding. The trials varied in how nausea and vomiting were recorded. To maximise the data available for the analysis, studies reporting nausea alone were pooled with studies reporting postoperative nausea and vomiting (PONV). Comparisons were described as statistically significant (at 5% level) when the credibility interval (CrI) did not cross 1 for odds ratio (OR) and zero for mean difference (MD). Trials making direct comparisons between the active interventions were also pooled in a meta-analysis using a random effects model. Sensitivity analyses were undertaken to explore the effect on 24-hour morphine consumption MTC results of study quality and classifying the treatments by individual drug rather than class of drug. In addition, a post hoc sensitivity analysis was undertaken to explore the effect of baseline morphine consumption on the MTC analysis for 24-hour morphine consumption.


Sixty relevant studies were identified, 40 were from the earlier review being updated and 20 were new studies. For morphine consumption, data were combined from 56 trials that randomised patients to four treatments, including placebo. When paracetamol, NSAIDs or COX-2 inhibitors were added to PCA morphine, there was a statistically significant reduction in morphine consumption: paracetamol (MD –6.34 mg; 95% CrI –9.02 to –3.65); NSAIDs (MD –10.18 mg; 95% CrI –11.65 to – 8.72); and COX-2 inhibitors (MD –10.92; 95% CrI –12.77 to –9.08). NSAIDs and COX-2 inhibitors were both significantly better than paracetamol, and there was no significant difference between NSAIDs and COX-2 inhibitors (MD –0.74; 95% CrI –3.03 to 1.56).

The sensitivity analyses for quality and baseline morphine consumption showed the results of the main analysis to be robust, though the results adjusted for baseline morphine consumption are probably a better estimate of the effect sizes. The analysis of individual drugs (as opposed to drug class) suggested that it was reasonable to group the drugs into three classes, though there appeared to be possible inconsistency across different NSAIDs.

Data were combined from 43 trials for nausea and PONV. There was a significant reduction in nausea and PONV with NSAIDs compared to placebo (OR 0.70; 95% CrI 0.53 to 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared to paracetamol or COX-2 inhibitors.

Data were combined from 19 trials for sedation for all four treatments. There was no statistically significant difference between any intervention and comparator. Compared to placebo, there was a trend towards increased sedation with paracetamol (OR 1.62; 95% CrI 0.32 to 5.02) and decreased sedation with NSAIDs (OR 0.53; 95% CrI 0.20 to 1.01) and COX-2 inhibitors (OR 0.63; 95% CrI 0.18 to 1.49). Surgical bleeding was not reported in any paracetamol studies and in a single COX-2 inhibitor study. Based on six trials (n = 695), 2.4% of participants receiving an NSAID experienced surgery-related bleeding compared to 0.4% with placebo.


There was a decrease in 24-hour morphine consumption, compared to placebo, ranging from 6.3 mg to 10.9 mg, when paracetamol, NSAID or COX-2 inhibitors were added to PCA morphine following surgery. When the three drug classes were compared to each other the differences in morphine consumption were small and unlikely to be of clinical significance. In addition, the benefits in terms of reduction of morphine-related adverse effects do not strongly favour one of the three non-opioid analgesics.

Implications for health care

All three non-opioid analgesics were effective at reducing PCA morphine consumption in the first 24 hours following major surgery. NSAIDs and COX-2 inhibitors were more effective than paracetamol, but the differences were small and probably of limited clinical significance, especially when baseline morphine consumption is taken into consideration. The difference between NSAIDs and COX-2 inhibitors was marginal and not statistically significant. The adjusted results suggest a mean difference of less than 2 mg of morphine over 24 hours when any of the drug classes was compared to the others. In terms of morphine-related adverse effects, which is the more clinically relevant outcome, the results do not strongly favour one class of non-opioid analgesic: NSAIDs were ranked highest for reducing the primary morphine-related adverse effects but they were only marginally better than COX-2 inhibitors and paracetamol. Any morphine-sparing effects of these non-opioid analgesics need to be balanced against any adverse effects related to the analgesics themselves. There were a small number of surgical bleeding events, gastrointestinal bleeding and oliguria for participants treated with an NSAID.

Taking the evidence as a whole, the uncertainty suggested by the size of the probabilities of being most effective, the small reduction in morphine consumption and the wide confidence intervals for adverse effects outcomes, there does not appear to be a strong case for recommending routine addition of any of the three non-opioids to PCA morphine in the 24 hours immediately after surgery. In addition, there does not appear to be a strong case for favouring one drug class above the others.

Recommendations for research

Given the overlap in the effects of the three analgesics, there does not appear to be a compelling case for a further trial. However, any future trials testing new analgesics in conjunction with morphine, following surgery, should focus on morphine-related adverse effects, ensuring that the power calculation is based on key morphine-related adverse effects rather than morphine consumption. Also, there would be value in exploring whether taking baseline morphine consumption into account alters the results for morphine-related adverse effects.


  • McDaid C, Maund E, Rice S, Wright K, Jenkins B, Woolacott N. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review. Health Technol Assess 2010;14(17). [PubMed: 20346263]

NIHR Health Technology Assessment programme

The Health Technology Assessment (HTA) programme, part of the National Institute for Health Research (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. ‘Health technologies’ are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care.

The research findings from the HTA programme directly influence decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC). HTA findings also help to improve the quality of clinical practice in the NHS indirectly in that they form a key component of the ‘National Knowledge Service’.

The HTA programme is needs led in that it fills gaps in the evidence needed by the NHS. There are three routes to the start of projects.

First is the commissioned route. Suggestions for research are actively sought from people working in the NHS, from the public and consumer groups and from professional bodies such as royal colleges and NHS trusts. These suggestions are carefully prioritised by panels of independent experts (including NHS service users). The HTA programme then commissions the research by competitive tender.

Second, the HTA programme provides grants for clinical trials for researchers who identify research questions. These are assessed for importance to patients and the NHS, and scientific rigour.

Third, through its Technology Assessment Report (TAR) call-off contract, the HTA programme commissions bespoke reports, principally for NICE, but also for other policy-makers. TARs bring together evidence on the value of specific technologies.

Some HTA research projects, including TARs, may take only months, others need several years. They can cost from as little as £40,000 to over £1 million, and may involve synthesising existing evidence, undertaking a trial, or other research collecting new data to answer a research problem.

The final reports from HTA projects are peer reviewed by a number of independent expert referees before publication in the widely read journal series Health Technology Assessment.

Criteria for inclusion in the HTA journal series

Reports are published in the HTA journal series if (1) they have resulted from work for the HTA programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors.

Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others.

The research reported in this issue of the journal was commissioned by the HTA programme as project number 08/114/01. The contractual start date was in February 2009. The draft report began editorial review in August 2009 and was accepted for publication in October 2009. As the funder, by devising a commissioning brief, the HTA programme specified the research question and study design. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Editor-in-Chief: Professor Tom Walley CBE

Series Editors: Dr Martin Ashton-Key, Dr Aileen Clarke, Professor Chris Hyde, Dr Tom Marshall, Dr John Powell, Dr Rob Riemsma and Professor Ken Stein

© 2010 Crown Copyright.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK56886


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