Abstract

Background

Postoperative administration of non‐steroidal anti‐inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, may reduce the incidence and severity of opioid‐induced adverse events (AEs).

Objectives

To assess the analgesic efficacy and adverse effects of single‐dose intravenous (IV) ibuprofen, compared with placebo or an active comparator, for moderate‐to‐severe postoperative pain in adults.

Search methods

We searched the following databases without language restrictions: CENTRAL, MEDLINE, Embase and LILACS on 10 June 2021. We checked clinical trials registers and reference lists of retrieved articles for additional studies.

Selection criteria

We included randomized trials that compared a single postoperative dose of intravenous (IV) ibuprofen with placebo or another active treatment, for treating acute postoperative pain in adults following any surgery.

Data collection and analysis

We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for review inclusion, assessed risk of bias, and extracted data.-Our primary outcome was the number of participants in each arm achieving at least 50% pain relief over a 4‐ and 6‐hour period.

Our secondary outcomes were time to, and number of participants using rescue medication; withdrawals due to lack of efficacy, adverse events (AEs), and for any other cause; and number of participants reporting or experiencing any AE, serious AEs (SAEs), and specific NSAID‐related or opioid‐related AEs.

We were not able to carry out any planned meta‐analysis. We assessed the certainty of the evidence using GRADE.

Main results

Only one study met our inclusion criteria, involving 201 total participants, mostly female (mean age 42 years), undergoing primary, unilateral, distal, first metatarsal bunionectomy (with osteotomy and internal fixation). Ibuprofen 300 mg, placebo or acetaminophen 1000 mg was administered intravenously to participants reporting moderate pain intensity the day after surgery. Since we identified only one study for inclusion, we did not perform any quantitative analyses. The study was at low risk of bias for most domains. We downgraded the certainty of the evidence due to serious study limitations, indirectness and imprecision.

Ibuprofen versus placebo

Findings of the single study found that at both the 4‐hour and 6‐hour assessment period, the proportion of participants with at least 50% pain relief was 32% (24/76) for those assigned to ibuprofen and 22% (11/50) for those assigned to placebo. These findings produced a risk ratio (RR) of 1.44 (95% confidence interval (CI) 0.77 to 2.66 versus placebo for at least 50% of maximum pain relief over the 4‐hour and 6‐hour period (very low‐certainty evidence).

Median time to rescue medication was 101 minutes for ibuprofen and 71 minutes for placebo (1 study, 126 participants; very low‐certainty evidence). The number of participants using rescue medication was not reported within the included study.

During the study (1 study, 126 participants), 58/76 (76%) of participants assigned to ibuprofen and 39/50 (78%) assigned to placebo reported or experienced any adverse event (AE), (RR 0.98, 95% CI 0.81 to 1.19; low‐certainty evidence).

No serious AEs (SAEs) were experienced (1 study, 126 participants; very low‐certainty evidence).

Ibuprofen versus active comparators

Ibuprofen (300 mg) was similar to the active comparator, IV acetaminophen (1000 mg) at 4 hours and 6 hours (1 study, 126 participants). For those assigned to active control (acetaminophen), the proportion of participants with at least 50% pain relief was 35% (26/75) at 4 hours and 31% (23/75) at 6 hours. At 4 hours, these findings produced a RR of 0.91 (95% CI 0.58 to 1.43; very low‐certainty evidence) versus active comparator (acetaminophen). At 6 hours, these findings produced a RR of 1.03 (95% CI 0.64 to 1.66; very low‐certainty evidence) versus active comparator (acetaminophen).

Median time to rescue medication was 101 minutes for ibuprofen and 125 minutes for the active comparator, acetaminophen (1 study, 151 participants; very low‐certainty evidence). The number of participants using rescue medication was not reported within the included study.

During the study, 58/76 (76%) of participants assigned to ibuprofen and 45/75 (60%) assigned to active control (acetaminophen) reported or experienced any AE, (RR 1.27, 95% CI 1.02 to 1.59; very low‐certainty evidence).

No SAEs were experienced (1 study, 151 participants; very low‐certainty evidence).

Authors' conclusions

There is insufficient evidence to support or refute the suggestion that IV ibuprofen is effective and safe for acute postoperative pain in adults. 

Author(s)

McKenzie C Ferguson, Roman Schumann, Sean Gallagher, Ewan D McNicol

Abstract

Plain language summary

What are the benefits and risks of a single injection of ibuprofen (an anti‐inflammation medicine) for relieving short‐term pain after surgery in adults? 

Key messages

‐ There is not enough evidence to determine whether intravenous (injection into a vein) ibuprofen is an effective treatment for adults with pain after surgery or if it can harm them. 

‐ It would be beneficial if future studies on this topic were well‐designed with a large number of patients to determine if ibuprofen is an effective treatment for the management of pain after surgery.

‐ More evidence is required to establish if ibuprofen causes serious unwanted effects.

Treating short‐term pain after surgery

Pain is common in the short term (within 6 hours) after surgery (postoperative pain). 

Non‐steroidal anti‐inflammatory drugs (NSAIDs, aspirin‐like drugs) are often delivered along with opioids (such as morphine) to treat this type of pain. However, NSAIDs can have side effects. NSAIDS (such as ibuprofen) may result in bleeding (e.g. at the site of an incision or wound) and may result in injury to the kidneys and gut. 

Patients need more and better treatment options to help manage short‐term pain after surgery. There is a lot of concern about using opioids to treat short‐term pain because of the risk that patients can develop unpleasant side effects or opioid over‐use disorder. It is therefore important to weigh the benefits and risks of NSAIDs when considering using them to reduce pain shortly after surgery.

What did we want to find out?

Ibuprofen is a NSAID that can be delivered intravenously. We wanted to know if intravenous ibuprofen (delivered by injection or drip) is a helpful treatment option to manage moderate‐to‐severe pain when patients cannot take medicines by mouth. 

What did we do?

To make the comparison fair, patients in the studies must all have had the same random chance (like the flip of a coin) to receive the ibuprofen or the other treatment. 

We searched the medical literature (clinical studies) up to June 2021, where intravenous ibuprofen was used to treat pain after surgery in adults (aged over 18) and compared against:

‐ a placebo (a control treatment, such as a bag of saline administered into a vein); or

‐ another medicine.

What did we find?

We found only one study which was suitable to include in our review. The study looked at the management of pain after bunionectomy. Bunionectomy is a surgery to remove a bunion at the base of the big toe. This study evaluated 201 people, mostly females. The study compared intravenous ibuprofen to:

‐ a placebo; or

‐ another medicine, acetaminophen (paracetamol).

We were most interested in learning how many people had their pain reduced by 50% (half) or more within 4 or 6 hours of surgery. 

Pain reduction

The study showed that:

‐ more people who received ibuprofen had their pain reduced by 50% (half) or more within 4 or 6 hours of surgery as compared to those who received placebo; and 

‐ there was little to no difference when ibuprofen was compared to another medicine, acetaminophen, i.e. the numbers of people with pain reduced by 50% (half) or more within 4 or 6 hours of surgery 

Need for extra pain medicines (rescue medication)

Rescue medicine is an extra pain medication if the study medication is not treating the patient's pain well enough. The time (in minutes) to needing rescue medication was longer (delayed) with use of ibuprofen or acetaminophen than for those who received placebo. 

Adverse events

There was not enough information in this study to assess side effects, but the rate at which they occurred appeared to be similar among all treatments. Very few patients dropped out because of side effects. This is usually the case in studies where patients are only in a study for a short period of time. 

What are the limitations of the evidence?

We only had results from one relatively small study. This limited our confidence in the evidence.

How up to date is this evidence?

The evidence is up to date to June 2021.

Author(s)

McKenzie C Ferguson, Roman Schumann, Sean Gallagher, Ewan D McNicol

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For adults with moderate‐to‐severe postoperative pain

There is insufficient evidence to support or refute the suggestion that single‐dose intravenous (IV) ibuprofen is safe and efficacious for treating acute postoperative pain. 

For clinicians

There is insufficient evidence to support or refute the suggestion that single‐dose IV ibuprofen is safe and efficacious for treating acute postoperative pain. Until more evidence is provided, clinicians need to reply on expert opinion.

For policymakers

There is insufficient evidence to support or refute the suggestion that single‐dose IV ibuprofen is safe and efficacious for treating acute postoperative pain. In the absence of evidence, policymakers should exercise caution when considering its use in postoperative guidelines for pain management. 

For funders

There is insufficient evidence to support or refute the suggestion that single‐dose IV ibuprofen is safe and efficacious for treating acute postoperative pain. At this time, parenteral ibuprofen (caldolor, USA) is not available as a generic product, whereas another widely available parenteral non‐steroidal anti‐inflammatory drug (NSAID), ketorolac, is available as a generic product. We did not aim to compare differences in safety or efficacy between different parenteral NSAIDs and how it may affect cost. Similarly, it is unclear whether the increased cost of parenteral formulations of ibuprofen versus oral formulations is offset by increased effectiveness and reduced overall costs.

Implications for research 

More studies are required to be able to more accurately estimate efficacy and safety of IV ibuprofen. To date, there is a lack of studies specifically assessing postoperative administration. 

Design

The lack of studies included in this review may be explained by several factors: 1) multimodal treatment approaches have become widely accepted given concerns regarding the safety of opioids and several studies did not meet the inclusion criteria for this review as they administered ibuprofen as part of a multimodal regimen; and 2) NSAIDs are frequently administered shortly before the end of surgery and we chose to exclude studies that administered ibuprofen pre‐ or intraoperatively. 

The study included in our review was designed to detect differences in efficacy between interventions. However, further studies that compare different doses of ibuprofen may establish whether doses lower than those currently employed are equally effective, particularly in elderly patients, where data from non‐randomized studies demonstrate higher adverse event (AE) rates. Serious AEs (SAEs) associated with NSAIDs were not reported in the included study, and overall are rare. There are several epidemiological studies that may more accurately determine the adverse profile of ibuprofen, particularly with respect to renal dysfunction, bleeding, cardiovascular events and delay of bone healing postoperatively.

Outcomes

Endpoints and the pain scoring scales used to assess them in this study have been extensively validated. The single included study assessed pain relief after administration of each intervention, an outcome shown to be clinically important to patients. Studies conducting cost‐benefit analyses may determine whether the reduced cost of parenteral ketorolac versus brand name IV ibuprofen is offset by increased AE rates and subsequently increased overall costs of care.

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