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

Key messages

· Ketorolac may reduce short-term pain after surgery by 50% (half) or more in more people than a placebo (dummy treatment).
· There may be little to no difference between ketorolac and other anti-inflammation medicines in the number of people whose pain is reduced by half or more.
· Ketorolac probably causes slightly more unwanted effects than placebo and other anti-inflammation medicines; more evidence is required to establish if it causes serious unwanted effects.

Treating short-term pain after surgery

It is common for people to feel pain in the short term (within six hours) after surgery. Often, medicines called non-steroidal anti-inflammatory drugs (NSAIDs) are given to relieve this pain.

NSAIDS work by stopping the body’s production of chemicals that cause inflammation and pain. A potential advantage of using NSAIDs is that they may limit the need for stronger pain-relief medicine such as opioids. Opioids can cause unwanted (adverse) events such as nausea and vomiting, constipation, breathing problems and allergic reactions. People may become addicted to opioids if they take a lot of them.

NSAIDs can also cause unwanted effects. These include bleeding at the site of the surgical wound, and potential injury to the kidneys and gut. 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?

We wanted to find out about the benefits and risks of using a specific NSAID, ketorolac, for relief of short-term pain after surgery. Ketorolac can be given as an injection, which may be useful when patients cannot take medicines by mouth.

What did we do?

We searched for studies that involved adults (aged over 18) and compared a single injection of ketorolac against:

· a placebo (dummy treatment); or
· another treatment.

We compared and summarized the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 12 studies that involved 1905 people in total. The studies investigated the treatment of pain after surgery on the abdomen, pelvis, teeth, bones, joints and muscles. Most studies (10) treated people with a dose of 30 milligrams of ketorolac. They compared ketorolac against:

· a placebo;
· another NSAID; or
· an opioid.

Here we present the findings from comparisons between ketorolac and placebo or other NSAIDs.

Pain reduction

The evidence suggests that:

· around three times more people may have their pain reduced by 50% (half) or more within six hours of surgery when treated with ketorolac rather than placebo; and
· there could be little to no difference between ketorolac and other NSAIDS in the number of people with pain reduced by 50% or more within four or six hours of surgery.

Need for extra pain medicines (rescue medication)

Ketorolac could delay the need for rescue medication compared to placebo or other NSAIDs. The evidence is not robust enough to show if fewer people need rescue medicine when treated with ketorolac.

Adverse effects

Ketorolac probably causes slightly more adverse effects than placebo and other NSAIDS. Serious adverse effects (such as blood collecting in the muscles around the abdomen, causing severe pain) were rare in the studies we found; the evidence suggested there may be little to no difference in the number of serious adverse events between ketorolac and placebo or other NSAIDS.

What are the limitations of the evidence?

Studies were small, and most may have been conducted in ways that could introduce errors into their results. This limited our confidence in the evidence.

How up to date is this evidence?

The evidence is up to date to April 2020.

Authors' conclusions: 

The amount and certainty of evidence for the use of intravenous ketorolac as a treatment for postoperative pain varies across efficacy and safety outcomes and amongst comparators, from very low to moderate. The available evidence indicates that postoperative intravenous ketorolac administration may offer substantial pain relief for most patients, but further research may impact this estimate. Adverse events appear to occur at a slightly higher rate in comparison to placebo and to other NSAIDs. Insufficient information is available to assess whether intravenous ketorolac has a different rate of gastrointestinal or surgical-site bleeding, renal dysfunction, or cardiovascular events versus other NSAIDs. There was a lack of studies in cardiovascular surgeries and in elderly populations who may be at increased risk for adverse events.

Read the full abstract...
Background: 

Postoperative pain is common and may be severe. 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 ketorolac, compared with placebo or an active comparator, for moderate to severe postoperative pain in adults.

Search strategy: 

We searched the following databases without language restrictions: CENTRAL, MEDLINE, Embase and LILACS on 20 April 2020. We checked clinical trials registers and reference lists of retrieved articles for additional studies.

Selection criteria: 

Randomized double-blind trials that compared a single postoperative dose of intravenous ketorolac 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. 
Our primary outcome was the number of participants in each arm achieving at least 50% pain relief over a four- and six-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 experiencing any AE, serious AEs (SAEs), and NSAID-related or opioid-related AEs.
For subgroup analysis, we planned to analyze different doses of parenteral ketorolac separately and to analyze results based on the type of surgery performed.
We assessed the certainty of evidence using GRADE.

Main results: 

We included 12 studies, involving 1905 participants undergoing various surgeries (pelvic/abdominal, dental, and orthopedic), with 17 to 83 participants receiving intravenous ketorolac in each study. Mean study population ages ranged from 22.5 years to 67.4 years. Most studies administered a dose of ketorolac of 30 mg; one study assessed 15 mg, and another administered 60 mg.

Most studies had an unclear risk of bias for some domains, particularly allocation concealment and blinding, and a high risk of bias due to small sample size. The overall certainty of evidence for each outcome ranged from very low to moderate. Reasons for downgrading certainty included serious study limitations, inconsistency and imprecision.

Ketorolac versus placebo

Very low-certainty evidence from eight studies (658 participants) suggests that ketorolac results in a large increase in the number of participants achieving at least 50% pain relief over four hours compared to placebo, but the evidence is very uncertain (risk ratio (RR) 2.81, 95% confidence interval (CI) 1.80 to 4.37). The number needed to treat for one additional participant to benefit (NNTB) was 2.4 (95% CI 1.8 to 3.7). Low-certainty evidence from 10 studies (914 participants) demonstrates that ketorolac may result in a large increase in the number of participants achieving at least 50% pain relief over six hours compared to placebo (RR 3.26, 95% CI 1.93 to 5.51). The NNTB was 2.5 (95% CI 1.9 to 3.7).

Among secondary outcomes, for time to rescue medication, moderate-certainty evidence comparing intravenous ketorolac versus placebo demonstrated a mean median of 271 minutes for ketorolac versus 104 minutes for placebo (6 studies, 633 participants). For the number of participants using rescue medication, very low-certainty evidence from five studies (417 participants) compared ketorolac with placebo. The RR was 0.60 (95% CI 0.36 to 1.00), that is, it did not demonstrate a difference between groups.

Ketorolac probably results in a slight increase in total adverse event rates compared with placebo (74% versus 65%; 8 studies, 810 participants; RR 1.09, 95% CI 1.00 to 1.19; number needed to treat for an additional harmful event (NNTH) 16.7, 95% CI 8.3 to infinite, moderate-certainty evidence). Serious AEs were rare. Low-certainty evidence from eight studies (703 participants) did not demonstrate a difference in rates between ketorolac and placebo (RR 0.62, 95% CI 0.13 to 3.03).

Ketorolac versus NSAIDs 
Ketorolac was compared to parecoxib in four studies and diclofenac in two studies. For our primary outcome, over both four and six hours there was no evidence of a difference between intravenous ketorolac and another NSAID (low-certainty and moderate-certainty evidence, respectively). Over four hours, four studies (337 participants) produced an RR of 1.04 (95% CI 0.89 to 1.21) and over six hours, six studies (603 participants) produced an RR of 1.06 (95% CI 0.95 to 1.19).

For time to rescue medication, low-certainty evidence from four studies (427 participants) suggested that participants receiving ketorolac waited an extra 35 minutes (mean median 331 minutes versus 296 minutes). For the number of participants using rescue medication, very low-certainty evidence from three studies (260 participants) compared ketorolac with another NSAID. The RR was 0.90 (95% CI 0.58 to 1.40), that is, there may be little or no difference between groups.  

Ketorolac probably results in a slight increase in total adverse event rates compared with another NSAID (76% versus 68%, 5 studies, 516 participants; RR 1.11, 95% CI 1.00 to 1.23; NNTH 12.5, 95% CI 6.7 to infinite, moderate-certainty evidence). Serious AEs were rare. Low-certainty evidence from five studies (530 participants) did not demonstrate a difference in rates between ketorolac and another NSAID (RR 3.18, 95% CI 0.13 to 76.99). Only one of the five studies reported a single serious AE.

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