Pre‐emptive and preventive NSAIDs for postoperative pain in adults undergoing all types of surgery

Brett Doleman; Jo Leonardi-Bee; Thomas P Heinink; Hannah Boyd-Carson; Laura Carrick; Rahil Mandalia; Jon N Lund; John P Williams

doi:10.1002/14651858.CD012978.pub2

. 2021 Jun 14;2021(6):CD012978. doi: 10.1002/14651858.CD012978.pub2

Pre‐emptive and preventive NSAIDs for postoperative pain in adults undergoing all types of surgery

Brett Doleman ^1,^✉, Jo Leonardi-Bee ², Thomas P Heinink ³, Hannah Boyd-Carson ⁴, Laura Carrick ⁵, Rahil Mandalia ⁶, Jon N Lund ⁷, John P Williams ¹

Editor: Cochrane Anaesthesia Group

PMCID: PMC8203105 PMID: 34125958

Abstract

Background

Postoperative pain is a common consequence of surgery and can have many negative perioperative effects. It has been suggested that the administration of analgesia before a painful stimulus may improve pain control. We defined pre‐emptive nonsteroidal anti‐inflammatories (NSAIDs) as those given before surgery but not continued afterwards and preventive NSAIDs as those given before surgery and continued afterwards. These were compared to a control group given the NSAIDs after surgery instead of before surgery.

Objectives

To assess the efficacy of preventive and pre‐emptive NSAIDs for reducing postoperative pain in adults undergoing all types of surgery.

Search methods

We searched the following electronic databases: CENTRAL, MEDLINE, Embase, AMED and CINAHL (up to June 2020). In addition, we searched for unpublished studies in three clinical trial databases, conference proceedings, grey literature databases, and reference lists of retrieved articles. We did not apply any restrictions on language or date of publication.

Selection criteria

We included parallel‐group randomized controlled trials (RCTs) only. We included adult participants undergoing any type of surgery. We defined pre‐emptive NSAIDs as those given before surgery but not continued afterwards and preventive NSAIDs as those given before surgery and continued afterwards. These were compared to a control group given the NSAIDs after surgery instead of before surgery. We included studies that gave the medication by any route but not given on the skin.

Data collection and analysis

We used the standard methods expected by Cochrane, as well as a novel publication bias test developed by our research group. We used GRADE to assess the certainty of the evidence for each outcome. Outcomes included acute postoperative pain (minimal clinically important difference (MCID): 1.5 on a 0‐10 scale), adverse events of NSAIDs, nausea and vomiting, 24‐hour morphine consumption (MCID: 10 mg reduction), time to analgesic request (MCID: one hour), pruritus, sedation, patient satisfaction, chronic pain and time to first bowel movement (MCID: 12 hours).

Main results

We included 71 RCTs. Seven studies are awaiting classification. We included 45 studies that evaluated pre‐emptive NSAIDs and 26 studies that evaluated preventive NSAIDs. We considered only four studies to be at low risk of bias for most domains. The operations and NSAIDs used varied, although most studies were conducted in abdominal, orthopaedic and dental surgery. Most studies were conducted in secondary care and in low‐risk participants. Common exclusions were participants on analgesic medications prior to surgery and those with chronic pain.

Pre‐emptive NSAIDs compared to post‐incision NSAIDs

For pre‐emptive NSAIDs, there is probably a decrease in early acute postoperative pain (MD ‐0.69, 95% CI ‐0.97 to ‐0.41; studies = 36; participants = 2032; I² = 96%; moderate‐certainty evidence). None of the included studies that reported on acute postoperative pain reported adverse events as an outcome. There may be little or no difference between the groups in short‐term (RR 1.00, 95% CI 0.34 to 2.94; studies = 2; participants = 100; I² = 0%; low‐certainty evidence) or long‐term nausea and vomiting (RR 0.85, 95% CI 0.52 to 1.38; studies = 5; participants = 228; I² = 29%; low‐certainty evidence). There may be a reduction in late acute postoperative pain (MD ‐0.22, 95% CI ‐0.44 to 0.00; studies = 28; participants = 1645; I² = 97%; low‐certainty evidence). There may be a reduction in 24‐hour morphine consumption with pre‐emptive NSAIDs (MD ‐5.62 mg, 95% CI ‐9.00 mg to ‐2.24 mg; studies = 16; participants = 854; I² = 99%; low‐certainty evidence) and an increase in the time to analgesic request (MD 17.04 minutes, 95% CI 3.77 minutes to 30.31 minutes; studies = 18; participants = 975; I² = 95%; low‐certainty evidence). There may be little or no difference in opioid adverse events such as pruritus (RR 0.40, 95% CI 0.09 to 1.76; studies = 4; participants = 254; I² = 0%; low‐certainty evidence) or sedation (RR 0.51, 95% CI 0.16 to 1.68; studies = 4; participants = 281; I² = 0%; low‐certainty evidence), although the number of included studies for these outcomes was small. No study reported patient satisfaction, chronic pain or time to first bowel movement for pre‐emptive NSAIDs.

Preventive NSAIDs compared to post‐incision NSAIDs

For preventive NSAIDs, there may be little or no difference in early acute postoperative pain (MD ‐0.14, 95% CI ‐0.39 to 0.12; studies = 18; participants = 1140; I² = 75%; low‐certainty evidence). One study reported adverse events from NSAIDs (reoperation for bleeding) although the events were low which did not allow any meaningful conclusions to be drawn (RR 1.95; 95% CI 0.18 to 20.68). There may be little or no difference in rates of short‐term (RR 1.26, 95% CI 0.49 to 3.30; studies = 1; participants = 76; low‐certainty evidence) or long‐term (RR 0.85, 95% CI 0.52 to 1.38; studies = 5; participants = 456; I² = 29%; low‐certainty evidence) nausea and vomiting. There may be a reduction in late acute postoperative pain (MD ‐0.33, 95% CI ‐0.59 to ‐0.07; studies = 21; participants = 1441; I² = 81%; low‐certainty evidence). There is probably a reduction in 24‐hour morphine consumption (MD ‐1.93 mg, 95% CI ‐3.55 mg to ‐0.32 mg; studies = 16; participants = 1323; I² = 49%; moderate‐certainty evidence). It is uncertain if there is any difference in time to analgesic request (MD 8.51 minutes, 95% CI ‐31.24 minutes to 48.27 minutes; studies = 8; participants = 410; I² = 98%; very low‐certainty evidence). As with pre‐emptive NSAIDs, there may be little or no difference in other opioid adverse events such as pruritus (RR 0.56, 95% CI 0.09 to 3.35; studies = 3; participants = 211; I² = 0%; low‐certainty evidence) and sedation (RR 0.84, 95% CI 0.44 to 1.63; studies = 5; participants = 497; I² = 0%; low‐certainty evidence). There is probably little or no difference in patient satisfaction (MD ‐0.42; 95% CI ‐1.09 to 0.25; studies = 1; participants = 72; moderate‐certainty evidence). No study reported on chronic pain. There is probably little or no difference in time to first bowel movement (MD 0.00; 95% CI ‐15.99 to 15.99; studies = 1; participants = 76; moderate‐certainty evidence).

Authors' conclusions

There was some evidence that pre‐emptive and preventive NSAIDs reduce both pain and morphine consumption, although this was not universal for all pain and morphine consumption outcomes. Any differences found were not clinically significant, although we cannot exclude this in more painful operations. Moreover, without any evidence of reductions in opioid adverse effects, the clinical significance of these results is questionable although few studies reported these outcomes. Only one study reported clinically significant adverse events from NSAIDs administered before surgery and, therefore, we have very few data to assess the safety of either pre‐emptive or preventive NSAIDs. Therefore, future research should aim to adhere to the highest methodology and be adequately powered to assess serious adverse events of NSAIDs and reductions in opioid adverse events.

Plain language summary

Ibuprofen‐like painkillers given before cutting the skin in surgery compared with given after cutting the skin in adults undergoing all types of surgery

We aimed to assess the effect of a single dose of a nonsteroidal anti‐inflammatory drug (NSAID: for example, ibuprofen) given before making the first cut during surgery (pre‐emptive NSAIDs) or given before the first cut and continued after surgery (preventive NSAIDs) on reducing pain in adults.

Review question We reviewed the evidence for NSAID painkillers when given before surgery compared to the same painkiller given only after the surgeon has cut the skin in adults undergoing all types of surgery.

Background Most people experience pain after surgery that requires strong opioid (similar to morphine) painkillers. These medications are associated with a number of side effects including reduced breathing, a slow heart rate, and low blood pressure, as well as vomiting, sleepiness, itching, and constipation. Reducing the amount of opioids needed after surgery can limit these side effects and improve the patient experience and outcomes. Compared to starting painkillers later, beginning painkillers before making the first cut for surgery may reduce pain sensitivity, and thus lessen the pain experienced. We wanted to find out whether giving NSAID painkillers before surgery was more effective than giving the same painkiller, at the same dose, after surgery.

Study characteristics We searched the medical literature for randomized controlled trials (a type of study in which participants are assigned to a treatment group using a random method). The evidence is current to June 2020. Patients were randomly allocated to one of two groups. One group was treated with NSAIDs before the surgeon cut the skin, whilst the other group was given the same medication after the surgeon cut the skin. We found 71 trials with patients aged 18 years or over who were undergoing many different operations. Nearly all patients were fit and healthy undergoing procedures in hospitals around the world.

Key results In 36 trials (2032 patients), use of pre‐emptive NSAIDs resulted in a small reduction in the pain experienced in the first six hours after surgery. No studies included serious side effects from NSAIDs as an outcome (bleeding, heart attacks or kidney failure). There was no difference in nausea and vomiting after surgery. In 28 studies (1645 patients), there was no difference in pain at 24 to 48 hours after surgery. In 16 studies (854 patients) there was a reduction in the amount of strong painkillers used after surgery and an increase in the time until patients needed these strong painkillers. Despite this, we found no reduction in the side effects from these strong painkillers (itching or sleepiness). No studies reported patient satisfaction, long‐term pain after surgery or the time until patients opened their bowels.

For preventive NSAIDs, in 18 studies (1140 patients), there was no difference in the pain experienced in the first six hours after surgery. One study reported bleeding after surgery requiring another operation and found no difference, although there were not enough events to be certain of this result. There was no difference in nausea and vomiting. In 21 studies (1441 patients), there was a reduction in pain at 24 to 48 hours after surgery and in 16 studies (1323 patients) a reduction in the amount of strong painkillers used after surgery. There was no difference in the time to requesting strong painkillers. There was no difference in itching, sleepiness or patient satisfaction. No study reported long‐term pain. There was no difference in time to first bowel movement.

Certainty of the evidence Although we found some differences in pain and painkiller usage, the certainty of the evidence ranged from very low to moderate. Also, any differences found were not large enough for patients to consider important. This was due to deficiencies in how the studies were conducted, the small numbers of patients recruited for some outcomes and differences in the results between studies, which means we are uncertain any differences we found are real and, therefore, future research is required.

Summary of findings

Background

This review contains text from a previous Cochrane protocol and review on pre‐emptive and preventive opioids (Doleman 2017a; Doleman 2018b). Throughout the review, we have used nonsteroidal anti‐inflammatory drugs (NSAIDs) as an umbrella term which consists of non‐selective NSAIDs (no specific enzyme activity) and cyclooxygenase‐2 (COX‐2) inhibitors (specific for COX‐2 enzyme).

Description of the condition

Postoperative pain is a common consequence of surgery that affects around 80% of patients. The severity of postoperative pain is variable, with 18% to 25% of patients suffering extreme pain (Apfelbaum 2003; Gerbershagen 2014). Pain can have deleterious effects during the postoperative period, including patient dissatisfaction (Myles 2000), interference with daily activities (Strassels 2002), pulmonary complications (Desai 1999), increases in the stress response to surgery (Desborough 2000), and an increased risk of chronic postsurgical pain (Kehlet 2006). Risk factors for severe postoperative pain include gender (Gerbershagen 2014), age (Gerbershagen 2014), the presence of preoperative pain (Gerbershagen 2014), preoperative anxiety and the type of surgery (Ip 2009). Intravenous opioids are commonly used to treat pain in the postoperative period (Benhamou 2008), however, their use is associated with many side effects such as vomiting, pruritus (itching), sedation (sleepiness) and patient concerns over addiction (Apfelbaum 2003). Therefore, alternative strategies to manage both postoperative pain and reduce postoperative opioid consumption may have important benefits for patients undergoing surgery (Frauenknecht 2019; Zhao 2004).

Description of the intervention

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are a commonly used analgesic during the peri‐operative period and include as examples: ibuprofen, naproxen, diclofenac and ketorolac. The mechanism of action of NSAIDs involves inhibition of cyclooxygenase (COX) enzymes, which are involved in the formation of hyperalgesic compounds called prostaglandins (Burian 2005). NSAIDs are effective in reducing postoperative pain, even when added to standard regimens including paracetamol (Ong 2010; Thybo 2019). Adverse events around the peri‐operative period include possible increases in bleeding (Warltier 2003), acute kidney injury and gastrointestinal ulceration (Gilron 2003). However, newer COX‐2‐specific agents that do not target gastrointestinal COX‐1 may offer lower occurrence of gastrointestinal ulceration compared with traditional NSAIDs (Jüni 2002), although studies have suggested an increased risk of cardiac events in high‐risk patients (Nussmeier 2005). Examples of these agents include celecoxib, parecoxib and rofecoxib.

Pre‐emptive analgesia involves the initiation of an analgesic agent (painkiller) prior to surgical incision (before the surgeon cuts the skin). It is thought that by initiating analgesic interventions before surgical injury, the analgesic can provide reductions in intra‐operative nociception to the central nervous system and, therefore, provide superior pain relief compared with the same analgesic given post‐incision (after the surgeon has cut the skin) (Kissin 2000). Preventive analgesia extends this definition to include increasing the intensity and duration of pre‐emptive analgesic interventions until final wound healing (Dahl 2011).

How the intervention might work

Surgical incision promotes changes in both the central and peripheral nervous system, called sensitization. Such sensitization can cause biochemical changes which manifest as hyperalgesia (the same pain stimulus causing increased pain), and allodynia (normal sensations causing pain). It is thought that by initiating analgesia before surgical incision, both peripheral and central sensitization can be reduced, resulting in reductions in intra‐operative nociception, and later, both acute and chronic postoperative pain. Preventive analgesia extends this reduction in sensitization to include the postoperative period. This enhanced definition came from an increased understanding of the development of persistent postsurgical pain, which is associated with postoperative sensitization. Postoperative sensitization may only be reduced by continuing analgesia longer into the postoperative period (Dahl 2011). As opioids are commonly used to treat pain postoperatively (Benhamou 2008), any reductions in opioid use may also result in a reduction in opioid adverse events (Doleman 2015b; Zhao 2004), and improve the patient experience.

Why it is important to do this review

Due to both its common occurrence (Apfelbaum 2003; Gerbershagen 2014), and potential deleterious effects during the postoperative period, reducing postoperative pain is an important clinical issue. A simple change in clinical practice, such as changing the timing of administration of analgesics, could have important implications for postoperative pain management. Moreover, such a change is cost‐neutral and therefore may benefit both anaesthetists in low‐income countries and those working within healthcare systems with finite resources (such as the National Health Service (NHS) in the United Kingdom).

The first review to examine the clinical effects of pre‐emptive analgesia showed pre‐emptive NSAIDs were ineffective in reducing pain scores or analgesic consumption in most of the included trials when compared to post‐incision NSAIDs (Møiniche 2002). A second review, published a few years later, demonstrated a lower analgesic consumption and delayed time to first analgesic request with pre‐emptive NSAIDs (Ong 2005). However, these reviews are now outdated and, importantly, did not evaluate reductions in opioid side effects (from reduced postoperative opioid consumption) and potential NSAID adverse events. This mandates an updated review of the evidence.

Objectives

To evaluate in adult participants undergoing all types of surgery, the effects of pre‐emptive and preventive nonsteroidal anti‐inflammatory drugs (NSAIDs) compared with post‐incision NSAIDs for reducing postoperative pain and opioid consumption.

Methods

Criteria for considering studies for this review

Types of studies

We included parallel‐group, randomized controlled trials (RCTs) only. We considered studies that did and did not use a double‐dummy placebo (for example, intervention group receives active drug before incision and placebo after incision; control group receives placebo before incision and active drug after incision). We excluded studies that included paediatric participants and pharmacokinetic studies not reporting any clinical outcomes.

Types of participants

Adult patients (18 years and above), both male and female, undergoing any type of surgery. We did not include studies that included both adult and paediatric participants.

Types of interventions

We compared both pre‐emptive nonsteroidal anti‐inflammatory drugs (NSAIDs) and preventive NSAIDs (intervention groups) with post‐incision NSAIDs (control group). We defined:

pre‐emptive NSAIDs as NSAIDs initiated before incision but not continued postoperatively;
preventive NSAIDs as NSAIDs initiated before surgical incision and continued postoperatively; and
post‐incision NSAIDs as the same analgesic intervention initiated after surgical incision, whether single dose (as comparator with pre‐emptive analgesia) or continued postoperatively (as comparator with preventive analgesia) (control group).

We only compared interventions if identical analgesics with identical dosages were used. In addition, we only included studies if concurrent use of other multimodal analgesic agents during the peri‐operative period were identical, in order to avoid confounding. If the studies reported multiple intervention subgroups that had comparable control groups (identical interventions), we combined these into one group using recommended methods (Higgins 2011a). We included all types of non‐selective NSAIDs and COX‐2 inhibitors, at any dose, via any route of systemic administration (oral and parenteral but not topical administration) and all types of regimen (pre‐emptive or preventive) in the analysis.

Types of outcome measures

Primary outcomes

Early acute postoperative pain (measured within six hours postoperatively using a validated pain scale; converted to a 0 to 10 scale where a 0 to 100 scale was used; and where multiple time points were reported, we included the earliest time point reported after post‐incision dosing).
Adverse events (reoperation for major bleeding within 30 days (yes/no)); acute kidney injury within 48 hours (defined using published criteria (Mehta 2007) (yes/no)); gastrointestinal ulceration or bleeding requiring endoscopy within 30 days (yes/no); myocardial infarction within 30 days (defined as two of three of the following: chest pain, electrocardiogram (ECG) changes indicating ischaemia, or > 20% rise in high‐sensitivity troponin (yes/no)). We reported these adverse events separately.

Secondary outcomes

Nausea and vomiting (self‐reported by the patient or requirement for anti‐emetic; we reported nausea and vomiting aggregated (yes/no)).
Late acute postoperative pain (measured at 24 to 48 hours postoperatively using a validated pain scale; converted to a 0 to 10 scale where a 0 to 100 scale was used; and where multiple time points were reported, we included the earliest time point reported).
24‐hour morphine consumption (mg) (if alternative opioids were used, we converted these to morphine‐equivalents using standard conversion factors (Doleman 2018a)).
Time to first analgesic request (minutes).
Pruritus (self‐reported by the patient (yes/no)).
Sedation (as defined in the individual studies (yes/no)).
Patient satisfaction (overall satisfaction self‐reported by the patient within 24 hours; converted to a 0 to 10 scale where a 0 to 100 scale was used).
Chronic pain (yes/no, measured three to six months postoperatively using a validated scale, such as the Visual Analogue Scale or the McGill Pain Questionnaire; we included the earliest time point closest to three months). We reported this outcome as a separate dichotomous and continuous outcome.
Time to first bowel movement (hours).

For the secondary outcomes where time points were not specified, we used the end point closest to two hours (one to six hours) to assess immediate short‐term effects, and the end point closest to 24 hours (six to 48 hours) to assess longer‐term effects. Outcomes did not form part of the study eligibility assessment, and so we included studies that met the participant, intervention and comparison criteria for inclusion in the review even if they reported no relevant outcomes. For the continuous outcomes, we considered the following to be minimal clinically important differences:

• Acute postoperative pain: 1.5 on a 0‐10 scale (Gallagher 2001; Myles 2017)

• 24‐hour morphine consumption: 10 mg reduction (Doleman 2015a)

• Time to analgesic request: one hour

• Time to first bowel movement: 12 hours.

Search methods for identification of studies

Electronic searches

We identified RCTs through literature searching designed to identify relevant trials as outlined in Chapter 4 of the Cochrane Handbook of Systematic Reviews of Interventions (Lefebvre 2019). We searched relevant systematic reviews for further trials (Møiniche 2002; Ong 2005). We did not apply restrictions due to language, publication status or publication year. We searched the following databases for relevant trials (Figure 1).

Cochrane Central Register of Controlled Trials (CENTRAL, latest Issue) in the Cochrane Library.
MEDLINE (Ovid SP, 1946 to June 2020).
Embase (Ovid SP, 1974 to June 2020).
CINAHL (1982 to June 2020).
AMED (1985 to June 2020).

We developed a draft search strategy for MEDLINE. We used this as the basis for the search strategies in the other databases listed (Appendix 1).

We scanned the following trials registries for ongoing and unpublished trials.

World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp/en);
ClinicalTrials.gov (clinicaltrials.gov).

Searching other resources

We conducted a search of the OpenSIGLE database to identify grey literature sources. We scanned the reference lists and citations of included trials and systematic reviews identified for further references to additional trials. When necessary, we contacted trial authors for additional information. In addition, we searched the following conference proceedings to identify further unpublished studies (all years considered).

World Congress on Pain (International Association for the Study of Pain).
Anaesthetic Research Society Meetings.
Association of Anaesthetists of Great Britain and Ireland Winter Symposium and Annual Congress.
American Society of Anesthesiologists Annual Meeting.
European Society of Anaesthesiologists Euroanaesthesia Conference.

The search strategy was developed in consultation with the Cochrane Anaesthesia Information Specialist.

Data collection and analysis

Selection of studies

We used two review authors (BD and JPW) to independently screen the identified studies using the inclusion criteria to assess eligibility. BD and JPW resolved any disagreements by consensus. If disagreement still existed following discussion, we consulted a third review author (JLB). BD and JPW used the information from the retrieved reports to help identify any duplicate publications, such as author name, study centre, type and dose of interventions used, and study dates. We linked any duplicate publications. We inputted details of all potentially eligible studies into PubMed to identify any retracted publications and we excluded these (Eisenach 2009).

Data extraction and management

We extracted data onto an electronic database using standardized data extraction forms (Appendix 2). We performed this independently using two review authors (BD and TH/HBC/LC), and resolved any disagreements by consensus. If disagreement still existed, we consulted a third review author (JPW). We performed the analysis using one review author (BD). Where possible, we translated non‐English language studies and extracted data following translation. If data were not contained within the original research report, we contacted the corresponding author, irrespective of the age of publication. We extracted the following information:

Bibliographic data, including date of completion/publication.
Country.
Publication status.
Source of funding.
Trial design, e.g. parallel‐group.
Study setting.
Number of participants randomized to each trial arm and number included in final analysis.
Eligibility criteria and key baseline participant data, including sex and age.
Details of treatment regimen received by each group.
Details of any co‐interventions.
Primary and secondary outcome(s) (with definitions and, where applicable, time points).
Outcome data for primary and secondary outcomes (by group).
Duration of follow‐up.
Number of withdrawals (by group) and number of withdrawals (by group) due to adverse events.
Adverse events.

Assessment of risk of bias in included studies

We assessed risk of bias in the included studies using the Cochrane tool for assessing risk of bias (Higgins 2011b). Two review authors (BD and JPW) independently undertook assessment of risk of bias and reached agreement by consensus. We assessed risk of bias for the domains of sequence generation, allocation concealment, blinding of participants, study personnel and outcome assessors, incomplete outcome data, selective outcome reporting and other sources of bias. We assessed each domain as being at low, unclear or high risk of bias (Higgins 2011b). We presented the results in both a risk of bias summary (Figure 2) and a risk of bias graph (Figure 3). We considered a study as being at low risk of bias if it was low risk for all domains (except selective reporting bias, as some studies were published before published protocols and clinical trial databases were standard) with no high‐risk domains and as being at high risk of bias if it was high risk in any domain. Studies were assessed as being at unclear risk if they were not classified into either low or high risk.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Measures of treatment effect

We presented dichotomous outcomes as risk ratios (RRs). For continuous outcomes, we presented these as mean differences (MDs). If non‐comparable scales were used across studies but still presented as continuous data, which we expected may be the case for chronic pain and patient satisfaction, we would have presented these as standardized mean differences (SMDs). We aimed to present the outcomes of time to first analgesic and time to first bowel movement as hazard ratios (HRs) (Tierney 2007). We presented the precision of effect estimates using 95% confidence intervals (CIs).

Unit of analysis issues

As we included parallel‐group RCTs only, unit of analysis issues were not a problem for the main analysis (Higgins 2011c). For the main results, we combined different dose subgroups into one treatment group, as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). If it was not possible to combine groups (for example, for continuous outcomes where the combined standard deviation (SD) could not be estimated), we treated these as separate studies and distributed the control group participants between these treatment groups to avoid analysing them twice (Higgins 2011c).

Dealing with missing data

We contacted corresponding authors for any data missing from the original publication, irrespective of publication date. If we did not receive a response, we extracted data from published graphs. If SDs were not reported, we attempted to calculate these from other reported statistics. If this was not possible, we estimated SDs from other studies with similar means. We estimated means from medians (equal if the assumption of normality holds) and SD from interquartile range (IQR)/1.35 (Higgins 2011a) or range (Hozo 2005). We did this as our previous review identified studies where medians were reported, and were more likely to be 'negative' than those reporting means, which could introduce bias into the results (Doleman 2018b). However, we assessed the robustness of our estimates by excluding all studies where means or SDs were estimated in a sensitivity analysis.

Assessment of heterogeneity

We assessed clinical heterogeneity by examining study characteristics, such as the type of population, type of surgery and the intervention used. We assessed statistical heterogeneity using the I² statistic. We used the following recommended cut‐off values in the interpretation of the I² statistic (Deeks 2011).

> 50% may represent moderate heterogeneity.
> 85% considerable heterogeneity.

In addition to the cut‐off values, we examined the direction of the effect in the individual studies. For clinically meaningful magnitudes of the pooled effect, we explored heterogeneity using meta‐regression when the criteria set out in Subgroup analysis and investigation of heterogeneity section were fulfilled.

Assessment of reporting biases

If we included 10 or more studies in the meta‐analysis, we assessed publication bias graphically using funnel plots and quantitatively using an updated publication bias test which uses inverse sample size on the Y axis and performs better than Egger’s linear regression test (Egger 1997) for outcomes dependent on baseline risk, such as pain and morphine consumption (Doleman 2020). This is due to correlation between standard errors and mean differences with these outcomes causing artefactual funnel plot asymmetry with Egger's test, which the use of inverse sample size corrects. Due to the low power of this test, we regarded P < 0.1 as evidence of imprecise study effects and possible publication bias.

Data synthesis

We used Review Manager 5 to aggregate study data (Review Manager 2014). We conducted separate analyses for pre‐emptive and preventive interventions. We aggregated data using the adapted DerSimonian and Laird random‐effects model (for continuous and categorical outcomes), as currently available in Review Manager 5. This is because we expected the treatment effect to vary with respect to the different populations within each study, and, therefore, there was no single underlying effect to estimate, making the random‐effects model more appropriate. We attempted to aggregate reported log hazard ratios and their associated standard errors using the generic inverse variance method, although no study adequately reported this.

Subgroup analysis and investigation of heterogeneity

If there were sufficient included studies, we conducted two separate subgroup analyses for the type of NSAIDs (non‐selective NSAIDs versus COX‐2 inhibitors) and trials with different baseline pain levels (mean pain scores in the control group of < 3 (mild), 3 to 6 (moderate) and > 6 (severe)) (Moore 2013). If we included 10 studies or more in a meta‐analysis and the included studies had a sufficient number of events, we explored reasons for heterogeneity by performing a restricted maximum likelihood, random‐effects meta‐regression where covariates were entered into the model separately based on type of anaesthesia and type of surgery (univariate analysis) (Thompson 2002). For dummy variables, we used the least effective subgroup as the reference category. We presented the R² analogue with a corresponding P value for each covariate. We used the Knapp‐Hartung method to calculate P values (as this method more appropriately uses the t‐distribution for the between‐study variance). We performed these analyses using the software STATA Version 16.1 (Stata 2020). If there was a low number of studies or events, or both, we only performed traditional subgroup analysis, and reported the P value for subgroup differences.

Sensitivity analysis

We performed a sensitivity analysis by restricting the analysis to studies at low risk of bias (defined as low risk for randomization and allocation concealment). As we judged studies that did not use a double‐dummy design as being at high risk of bias for blinding, we assessed the impact of excluding these from the analysis. We also performed a further sensitivity analysis by excluding studies where means and SDs were estimated (both where SDs were estimated from other studies and where means and/or SDs were estimated from median and IQR). As a further sensitivity analysis, we repeated analysis assuming excluded participants suffered an event to assess the robustness of the findings. Furthermore, we performed sensitivity analyses by excluding studies with a low sample size (< 50 participants).

Summary of findings and assessment of the certainty of the evidence

We presented outcomes in a summary of findings table. We produced two summary of findings tables, one for each comparison.

Pre‐emptive NSAIDs versus single dose post‐incision NSAIDs.
Preventive NSAIDs versus continuous post‐incision NSAIDs.

The outcomes presented in the summary of findings table for each comparison included: early acute postoperative pain; adverse events; nausea and vomiting; late acute postoperative pain; 24‐hour morphine consumption and time to first analgesic request. We did not include chronic pain as no studies reported this outcome. We presented these outcomes using the GRADE approach (Schünemann 2011). We downgraded the certainty of evidence from high‐certainty to moderate‐, low‐ or very low‐certainty. Downgrading was undertaken independently by two review authors (BD and JPW) and agreement reached by consensus. Characteristics of the evidence that caused downgrading included:

limitations in the design and implementation of available studies, suggesting a high likelihood of bias (for example, studies not using a double‐dummy placebo design);
indirectness of evidence (indirect population, intervention, control or outcomes);
inconsistency of results (considerable heterogeneity not explained by meta‐regression or subgroup analysis);
imprecision of results (wide confidence intervals);
evidence of publication bias from asymmetry of the funnel plot.

Results

Description of studies

Results of the search

Searching of electronic databases yielded 7749 studies (Figure 1). We found another study from clinical trial databases, a further three studies from conference proceedings and seven from reference list searches. We reviewed 98 full‐text articles and 27 were not included (Excluded studies).

Included studies

Following full‐text review, we included 71 studies (Characteristics of included studies) which satisfied our inclusion criteria.

Participants and surgery

The types of surgery included were diverse. We included 10 studies performed in dental surgery, one study included hand surgery, four in general/colorectal surgery, four in total hip arthroplasty, one in total knee arthroplasty, four in laparoscopic cholecystectomy, three in laparoscopic gynaecological surgery, five in minor orthopaedic surgery, four in laparoscopic or open gynaecological procedures, three in breast surgery, seven in hysterectomy, six in spinal surgery, one in abdominal or thoracic surgery, one in laparoscopic hernia repair, five in joint arthroscopy, one in varicocelectomy, one in laparotomy, one in lung resection, one in thoracotomy, one in mandible open reduction and internal fixation (ORIF), one in diagnostic laparoscopy, two in septo/rhinoplasty, one in spinal, breast and orthopaedic surgery, one in tonsillectomy, one in major plastic surgery and one in thyroid surgery. Seventeen studies included female participants only and one included male participants only. Most studies were conducted in low‐risk participants who were American Society of Anesthesiologists grade (ASA) 1 or 2 and seven included ASA 1‐3 participants, whilst others did not specify any exclusions on the basis of ASA grade.

Settings

Most studies were conducted in secondary care although other settings included dental clinics or dental medical schools. In terms of countries in which the trials were conducted, these included: one in Peru, four in the UK, one in Spain, four in India, 12 in China, three in France, two in Ireland, one in Denmark, six in the USA, three in Italy, one in Mexico, four in Germany, seven in Turkey, two in Romania, three in Poland, three in Austria, one in Australia, two in Japan, one in Iran, one in Canada, one in Northern Ireland, one in Greece, one in Finland, one in Sweden, one in Belgium, one in Indonesia, one in Thailand and two studies where the country was unclear.

Interventions

We included 52 studies which studied non‐selective NSAIDs and 19 which studied COX‐2 inhibitors. We included 45 studies which were pre‐emptive (single‐dose intervention not continued postoperatively) and 26 studies were preventive (intervention continued postoperatively).

Comparators

All included studies gave identical post‐incision doses as those that did not were excluded. In terms of post‐incision dose timing, 53 studies gave post‐incision doses postoperatively or at the end of surgery and 18 studies gave doses intraoperatively.

Funding

Many studies did not report sources of funding or stated no funding; overall, the total was 56 studies. Eleven studies specified that they received non‐industry funding and three studies reported industry funding. One study appeared to have authors who were pharmaceutical company employees.

Postoperative opioids and concurrent analgesia

The included studies used a diverse range of opioids for postoperative analgesia so we used conversion factors to calculate intravenous (IV) morphine equivalents. We included 16 studies which used no postoperative opioids or their use was not reported. Seventeen studies used patient controlled analgesia (PCA) morphine, one used nalbuphine, two used intramuscular (IM)/IV morphine, five used IV or IM pethidine, one used IV fentanyl and morphine, two used IV fentanyl, one used fentanyl PCA, one used buprenorphine, one used an IV morphine infusion, five used a tramadol PCA/IV, one used oral oxycodone, three used IV/PCA piritramide, two used oral or IV tramadol, one used IV and subcutaneous (SC) morphine, one used IV papaveretum, one used IV morphine and pethidine, one used IV fentanyl and codeine, one used cyclimorph and codeine, one used a diamorphine PCA, one used IV/IM oxycodone, one used dextropropoxyphene, one used sufentanil and tramadol, one used fentanyl, hydrocodone and morphine PCA, one used PCA butorphanol, one used a sufentanil PCA and one study used an unspecified analgesic.

In terms of concurrent analgesia, 52 studies reported no concurrent multimodal analgesia or did not mention any in the manuscript. Two studies used paracetamol and NSAIDs, two used NSAIDs which were different NSAIDs from the intervention, one used nurse‐controlled NSAIDs which were the same as the intervention NSAID, one used metamizole, 10 used paracetamol, one used codeine and NSAIDs, one used paracetamol, tramadol and metamizole and one used paracetamol, NSAIDs and codeine.

Excluded studies

We excluded 20 studies (Characteristics of excluded studies) which did not satisfy our inclusion criteria. Three studies were excluded because they were cross‐over trials. Seven studies included different doses of pre‐emptive or preventive versus post‐incision interventions. Two studies were excluded because they studied combination therapy rather than just NSAIDs/COX‐2 inhibitors. Two studies were excluded as they did not have any post‐incision group. Four studies were excluded as they included paediatric participants. Two studies were excluded as interventions had different routes of administration and were, therefore, not comparable.

Studies awaiting classification

There were seven studies (Characteristics of studies awaiting classification) awaiting classification. We were unable to translate two studies. We were unable to obtain the full text of another five studies via the British Library or contacting the study authors.

Risk of bias in included studies

Risk of bias assessments were conducted for the following domains.

Allocation

We included 31 studies which did not report details for randomization so were rated as having unclear risk. Nine studies used a random number chart or table, 27 used computer‐generated randomization, two used a random draw of envelopes or lots, one used block randomization and one used a random number generator so all of these studies were deemed as having low risk of bias. In terms of allocation concealment, 44 studies did not report their method of allocation concealment and four studies did not include enough details so both were deemed as having unclear risk of bias. In addition, a further nine studies reported envelopes but not enough details on envelope safeguards so were also deemed as having unclear risk of bias. Nine studies used third parties for randomization or allocation was pharmacy‐controlled so were deemed as having low risk of bias, whilst five studies reported sealed, sequentially numbered and opaque envelopes so were also deemed as having low risk of bias for allocation concealment.

Blinding

We included 14 studies which did not report the use of a double‐dummy placebo so were regarded as having high risk of bias for blinding. Fifty‐five studies used a double‐dummy placebo so were deemed as having low risk of bias. In two studies, it was unclear if a double‐dummy placebo had been used so they were considered as having unclear risk of bias for this domain.

In terms of blinding of outcome assessment, two studies were regarded as high risk from the lack of blinding of post‐incision dosing. Thirty‐seven studies used blinded outcome assessment and were deemed at low risk. Twenty‐five studies did not mention any outcome assessment blinding and were therefore deemed as having unclear risk of bias for this domain. Seven studies used participant self‐report for outcome assessment or outcomes were likely blinded from the details given, so these were deemed as having low risk for blinding of outcome assessment.

Incomplete outcome data

We included 15 studies which had low dropout rates or dropouts equal in numbers and reasons which were, therefore, regarded as low risk and 30 studies analysed all enrolled participants so were also at low risk of bias. Nine studies had unclear risk as it was unclear which to which group dropouts belonged or the study did not mention dropouts. We included 13 studies which were at high risk of bias due to a high number of dropouts which could bias results or an extreme dropout which could change results. Three studies used intention‐to‐treat analysis so were deemed as having low risk of bias.

Selective reporting

We included 53 studies which did not have a published protocol or clinical trial registration so were regarded as having unclear risk for selective outcome reporting. Ten studies did not report outcomes mentioned in the methods and were therefore deemed at high risk of bias for selective outcome reporting. One study used retrospective registration so was deemed at unclear risk for selective outcome reporting. Two studies pre‐registered the trial on a clinical trials database but did not fully report all prespecified outcomes so were deemed as having high risk of bias. Two studies with a protocol registration number that we could not locate were considered at unclear risk of bias and three studies reported all prespecified outcomes so were considered at low risk of bias.

Other potential sources of bias

We included five studies which had no details on baseline characteristics so were deemed at unclear risk of other bias and one study had industry funding but, because the extent of involvement was unclear, it was considered as having unclear risk of bias. Another 16 studies had disparities in baseline characteristics which could have affected pain so were deemed at high risk. We also judged one study as having high risk as the authors appeared to be pharmaceutical company employees. We included 48 studies which had no differences in baseline characteristics or industry funding so these were deemed at low risk of bias for other sources of bias.

Effects of interventions

See: Table 1; Table 2

Summary of findings 1. Summary of findings.

Pre‐emptive NSAIDs compared with post‐incision NSAIDs for postoperative pain
Patient or population: adults undergoing surgery Settings: secondary care and dental clinics Intervention: pre‐emptive NSAIDs Comparison: post‐incision NSAIDs
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Post‐incision NSAIDs	Pre‐emptive NSAIDs
Early acute postoperative pain (within 6 hours postoperatively using a validated pain scale: 0, no pain to 10, maximum pain)	The mean pain ranged across post‐incision groups from 0.32 to 6.37	Overall MD ‐0.69 (95% CI ‐0.97 to ‐0.41) Mild pain MD ‐0.24 (95% CI ‐0.51 to 0.03) Moderate pain MD ‐1.19 (95% CI ‐1.52 to ‐0.86) Severe pain MD ‐1.44 (95% CI ‐2.28 to ‐0.59)		2032 (36)	⊕⊕⊕⊝ moderate¹	Results not clinically significant
Adverse events	N/A	N/A	N/A	N/A	N/A	No study reported this outcome
Nausea and vomiting (1‐6 hours postoperatively)	120 per 1000	120 per 1000 (41 to 353)	RR 1.00 (0.34 to 2.94)	100 (2)	⊕⊕⊝⊝ low²
Nausea and vomiting (6‐48 hours postoperatively)	336 per 1000	278 per 1000 (175 to 464)	RR 0.85 (0.52 to 1.38)	228 (5)	⊕⊕⊝⊝ low²
Late acute postoperative pain (24‐48 hours postoperatively using a validated pain scale: 0, no pain to 10, maximum pain)	The mean pain ranged across post‐incision groups from 0.25 to 3.49	Overall MD ‐0.22 (95% CI ‐0.44 to 0.00) Mild pain MD ‐0.14 (95% CI ‐0.37 to 0.10) Moderate pain MD ‐0.77 (95% CI ‐1.08 to 0.47)		1645 (28)	⊕⊕⊝⊝ low³	Results not clinically significant
24‐hour morphine consumption (mg)	The mean morphine consumption ranged across post‐incision groups from 1.97 mg to 122.75 mg	Overall MD ‐5.62 mg (95% CI ‐9.00 mg to ‐2.24 mg) Low consumption MD ‐2.66 mg (95% CI ‐4.54 mg to ‐0.79 mg) Medium consumption MD ‐5.46 mg (95% CI ‐10.73 mg to ‐0.19 mg) High consumption MD ‐15.22 mg (95% CI ‐29.67 mg to ‐0.77 mg)		854 (16)	⊕⊕⊝⊝ low³	Results not clinically significant
Time to first analgesic request (mean time in minutes)	The mean time ranged across post‐incision groups from 29.6 minutes to 1146 minutes	MD 17.04 minutes (95% CI 3.77 minutes to 30.31 minutes)		975 (18)	⊕⊕⊝⊝ low³
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
GRADE Working Group grades of evidence High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: We are very uncertain about the estimate.

Preventive NSAIDs compared with post‐incision NSAIDs for postoperative pain
Patient or population: adults undergoing surgery Settings: secondary care and dental clinics Intervention: preventive NSAIDs Comparison: post‐incision NSAIDs
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Post‐incision NSAIDs	Preventive NSAIDs
Early acute postoperative pain (within 6 hours postoperatively using a validated pain scale: 0, no pain to 10, maximum pain)	The mean pain ranged across post‐incision groups from 0.18 to 6.42	Overall MD ‐0.14 (95% CI ‐0.39 to 0.12) Mild pain MD ‐0.04 (95% CI ‐0.31 to 0.24) Moderate pain MD ‐0.24 (95% CI ‐0.92 to 0.45) Severe pain MD ‐0.80 (95% CI ‐1.23 to ‐0.37)		1140 (18)	⊕⊕⊝⊝ low¹
Adverse events (Re‐operation for bleeding (reoperation for major bleeding within 30 days (yes/no)))	25 per 1000	49 per 1000 (5 to 517)	RR 1.95 (0.18 to 20.68)	81 (1)	⊕⊕⊝⊝ verylow²	Study performed in tonsillectomy so unclear for other operations. Other adverse events not reported
Nausea and vomiting (1‐6 hours postoperatively)	162 per 1000	205 per 1000 (79 to 535)	RR 1.26 (0.49 to 3.30)	76 (1)	⊕⊕⊕⊝ low³
Nausea and vomiting (6‐48 hours postoperatively)	245 per 1000	282 per 1000 (159 to 299)	RR 0.89 (0.65 to 1.22)	456 (8)	⊕⊕⊝⊝ low⁴
Late acute postoperative pain (24‐48 hours postoperatively using a validated pain scale: 0, no pain to 10, maximum pain)	The mean pain ranged across post‐incision groups from 0.42 to 4.6	Overall MD ‐0.33 (95% CI ‐0.59 to ‐0.07) Mild pain MD ‐0.33 (95% CI ‐0.62 to ‐0.05) Moderate pain MD ‐0.23 (95% CI ‐0.65 to 0.19)		1441 (21)	⊕⊕⊝⊝ low¹	Results not clinically significant
24‐hour morphine consumption (mg)	The mean morphine consumption ranged across post‐incision groups from 1.08 mg to 42.31 mg	Overall MD ‐1.93 mg (95% CI ‐3.55 mg to ‐0.32 mg) Low consumption MD ‐0.32 mg (95% CI ‐0.40 mg to ‐0.24 mg) Medium consumption MD ‐3.77 mg (95% CI ‐7.27 mg to ‐0.26 mg)		1323 (16)	⊕⊕⊕⊝ moderate⁵	Results not clinically significant
Time to first analgesic request (mean time in minutes)	The mean time ranged across post‐incision groups from 3.15 minutes to 523.1 minutes	MD 8.51 minutes (95% CI ‐31.24 minutes to 48.27 minutes)		410 (8)	⊕⊝⊝⊝ very low⁶
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
GRADE Working Group grades of evidence High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: We are very uncertain about the estimate.

Date form completed(dd/mm/yyyy)
Name/ID of person extracting data
Report title (title of paper/abstract/report that data are extracted from)
Report ID (ID for this paper/abstract/report)
Reference details
Report author contact details
Publication type (e.g. full report, abstract, letter)
Study funding sources (including role of funders)
Possible conflicts of interest (for study authors)
Notes:

Study Characteristics	Eligibility criteria (Insert eligibility criteria for each characteristic as defined in the protocol)		Yes	No	Unclear	Location in text (pg & /fig/table)
Type of study	Randomized Controlled Trial
Type of study	Controlled Clinical Trial (quasi‐randomized trial)
Participants
Types of intervention
Types of outcome measures
INCLUDE		EXCLUDE
Reason for exclusion
Notes:

	Description Include comparative information for each group (i.e. intervention and controls) if available	Location in text (pg & ¶/fig/table)
Population description (from which study participants are drawn)
Setting (including location and social context)
Inclusion criteria
Exclusion criteria
Method/s of recruitment of participants
Informed consent obtained	Yes No Unclear
Notes:

	Descriptions as stated in report/paper	Location in text (pg & ¶/fig/table)
Aim of study
Design(e.g. parallel‐group, cross‐over, cluster)
Unit of allocation (by individuals, cluster/groups or body parts)
Start date
End date
Total study duration
Ethical approval needed/ obtained for study	Yes No Unclear
Notes:

Domain	Risk of bias			Support for judgement	Location in text (pg & ¶/fig/table)
Domain	Low‐risk	High‐risk	Unclear	Support for judgement	Location in text (pg & ¶/fig/table)
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)				Outcome group: All/
(if required)				Outcome group:
Blinding of outcome assessment (detection bias)				Outcome group: All/
(if required)				Outcome group:
Incomplete outcome data (attrition bias)
Selective outcome reporting? (reporting bias)
Other bias
Notes:

	Description as stated in report/paper	Location in text (pg & ¶/fig/table)
Total no. randomized (or total pop. at start of study for NRCTs)
Clusters (if applicable, no., type, no. people per cluster)
Baseline imbalances
Withdrawals and exclusions (if not provided below by outcome)
Age
Sex
Race/ethnicity
Severity of illness
Comorbidities
Other treatment received(additional to study intervention)
Other relevant sociodemographics
Subgroups measured
Subgroups reported
Notes:

	Description as stated in report/paper	Location in text (pg & ¶/fig/table)
Group name
No. randomized to group (specify whether no. people or clusters)
Theoretical basis(include key references)
Description(include sufficient detail for replication, e.g. content, dose, components)
Duration of treatment period
Timing(e.g. frequency, duration of each episode)
Delivery(e.g. mechanism, medium, intensity, fidelity)
Providers (e.g. no., profession, training, ethnicity etc. if relevant)
Co‐interventions
Economic variables(i.e. intervention cost, changes in other costs as result of intervention)
Resource requirements to replicate intervention (e.g. staff numbers, cold chain, equipment)
Notes:

	Description as stated in report/paper	Location in text (pg & ¶/fig/table)
Outcome name
Time points measured
Time points reported
Outcome definition(with diagnostic criteria if relevant)
Person measuring/reporting
Unit of measurement (if relevant)
Scales: upper and lower limits(indicate whether high or low score is good)
Is outcome/tool validated?	Yes No Unclear
Imputation of missing data (e.g. assumptions made for ITT analysis)
Assumed risk estimate (e.g. baseline or population risk noted in Background)
Power
Notes:

	Description as stated in report/paper				Location in text (pg & ¶/fig/table)
Comparison
Outcome
Subgroup
Time point (specify whether from start or end of intervention)
Results	Intervention		Comparison
	No. events	No. participants	No. events	No. participants

No. missing participants and reasons
No. participants moved from other group and reasons
Any other results reported
Unit of analysis(by individuals, cluster/groups or body parts)
Statistical methods used and appropriateness of these methods(e.g. adjustment for correlation)
Reanalysis required?(specify)	Yes No Unclear
Reanalysis possible?	Yes No Unclear
Reanalysed results
Notes:

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Early acute postoperative pain (within 6 hours postoperatively)	36	2032	Mean Difference (IV, Random, 95% CI)	‐0.69 [‐0.97, ‐0.41]
1.2 Nausea and vomiting (short‐term)	2	100	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.34, 2.94]
1.3 Nausea and vomiting (long‐term)	5	228	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.52, 1.38]
1.4 Late acute postoperative pain (24‐48 hours postoperatively)	28	1645	Mean Difference (IV, Random, 95% CI)	‐0.22 [‐0.44, 0.00]
1.5 24‐hour morphine consumption (mg)	16	854	Mean Difference (IV, Random, 95% CI)	‐5.62 [‐9.00, ‐2.24]
1.6 Time to first analgesic request (minutes)	18	975	Mean Difference (IV, Random, 95% CI)	17.04 [3.77, 30.31]
1.7 Pruritus (long‐term)	4	254	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.09, 1.76]
1.8 Sedation (long‐term)	4	281	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.16, 1.68]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Early acute postoperative pain (within 6 hours postoperatively)	18	1140	Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.39, 0.12]
2.2 Re‐operation for bleeding	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.3 Nausea and vomiting (short‐term)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.4 Nausea and vomiting (long‐term)	8	456	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.65, 1.22]
2.5 Late acute postoperative pain (24‐48 hours postoperatively)	21	1441	Mean Difference (IV, Random, 95% CI)	‐0.33 [‐0.59, ‐0.07]
2.6 24‐hour morphine consumption (mg)	16	1323	Mean Difference (IV, Random, 95% CI)	‐1.93 [‐3.55, ‐0.32]
2.7 Time to first analgesic request (minutes)	8	410	Mean Difference (IV, Random, 95% CI)	8.51 [‐31.24, 48.27]
2.8 Pruritus (long‐term)	3	211	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.09, 3.35]
2.9 Sedation (long‐term)	5	497	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.44, 1.63]
2.10 Patient satisfaction	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.11 Time to bowel movement (hours)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

Have important populations been excluded from the study?(consider disadvantaged populations, and possible differences in the intervention effect)	Yes No Unclear
Is the intervention likely to be aimed at disadvantaged groups?(e.g.lower socioeconomic groups)	Yes No Unclear
Does the study directly address the review question? (any issues of partial or indirect applicability)	Yes No Unclear
Notes:

	Description as stated in report/paper	Location in text (pg & ¶/fig/table)
Key conclusions of study authors
References to other relevant studies
Correspondence required for further study information(from whom, what and when)
Notes:

*Study characteristics*
Methods	Study design: parallel‐group randomized controlled trial Sample size: 60 Country: Peru Setting: dental clinic Dates conducted: November 2013 to July 2014 Postoperative opioid used and delivery: none Pain score collection: researcher Concurrent postoperative analgesics: paracetamol or NSAID
Participants	Inclusion criteria ASA 1 Aged 18 to 45 years old Complete primary education Undergoing simple dental extraction for dental caries and asymptomatic at the time of extraction with a previous history of extraction Exclusion criteria Refused study participation Contraindication to extraction or study drugs Pregnancy or breast‐feeding Patients receiving anaesthesia, sedatives, paracetamol, NSAIDs, tricyclic antidepressants, opioids, corticosteroids, anticonvulsants, phenothiazines, alcohol or caffeine 48 hours before the extraction Intellectual disability Procedure could not be performed Exceeded two tubes of anaesthetic (> 3.6 mL) to achieve adequate anaesthesia Pain more than 70 mm (on a 100 mm VAS) pre‐extraction Procedures exceeded 20 minutes Participants who did not fill in the measuring instrument correctly Participants who did not comply with the instructions, abandoned the study, did not attend postoperative control or those who presented with any of the following post‐extraction complications: haemorrhage, infection, alveolitis, soft tissue lesions, bone or adjacent parts
Interventions	Group Prophylactic (30 participants): naproxen sodium 550 mg PO 30 minutes before the procedure, then every 12 hours for 4 doses Group Continuous (30 participants): naproxen sodium 550 mg PO 20 minutes after the procedure, then every 12 hours for 4 doses
Outcomes	Postoperative pain (0‐100 mm VAS at 1, 8 and 24 hours) Adverse effects (no details given)
Notes	Funding: not reported Declarations of interest: not reported Authors contacted: no Other: article in Spanish. Unpublished thesis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Unclear details. Quote: "Patients were randomly assigned".
Allocation concealment (selection bias)	Unclear risk	No mention
Blinding of participants and personnel (performance bias) All outcomes	High risk	No mention of double‐dummy placebo. Quote: "Naproxen sodium 550 mg was administered orally 30 minutes before the procedure, then every 12 hours until the 4 doses".
Blinding of outcome assessment (detection bias) All outcomes	High risk	Likely unblinded from above information
Incomplete outcome data (attrition bias) All outcomes	Low risk	Three excluded for alveolitis unlikely to bias results as this would cause confounding from increased pain. Quote: "Three people were eliminated by alveolitis".
Selective reporting (reporting bias)	Unclear risk	No registration or protocol. Unpublished thesis
Other bias	Unclear risk	No detailed information on baseline characteristics

Study	Reason for exclusion
Bridgman 1996	Cross‐over trial
Castiglione 1997	Two doses in pre‐emptive versus one in post‐incision
Espinet 1996	NSAID in combination with epidural anaesthesia
Hill 1987	No post‐incision group
Hou 2019	Pre‐emptive group had higher dose
Jung 2003	Paediatric participants included
Jung 2005	Paediatric participants included
Lau 2009	Cross‐over trial
Liu 1997	Same drug, different transdermal locations on the body (interventions not comparable)
Liu 2018	Different doses
Nelson 1993	Pre‐emptive group had higher dose
Nordbladh 1991	Paediatric participants included
Ramirez 2009	Paediatric participants included
Rosaeg 2001	Three pre‐emptive interventions studied
Sai 2001	No post‐incision group
Settecase 2002	Different doses
Turaga 2008	Different doses
Wuolijoki 1987	Different routes of administration
Zhu 2020	Pre‐emptive group had higher dose
Zor 2014	Cross‐over trial

PERMALINK

Pre‐emptive and preventive NSAIDs for postoperative pain in adults undergoing all types of surgery

Brett Doleman

Jo Leonardi-Bee

Thomas P Heinink

Hannah Boyd-Carson

Laura Carrick

Rahil Mandalia

Jon N Lund

John P Williams

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

1.

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

2.

3.

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

Included studies

Participants and surgery

Settings

Interventions

Comparators

Funding

Postoperative opioids and concurrent analgesia

Excluded studies

Studies awaiting classification

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings 1. Summary of findings.

Summary of findings 2. Summary of findings.

Pre‐emptive NSAIDs versus post‐incision NSAIDs

Primary outcomes

1. Early acute postoperative pain (measured within six hours postoperatively)

1.1. Analysis.

4.

5.