Evaluation of analgesic efficacy of intravenous ketorolac for acute postoperative pain in adults

Intravenous administration of ketorolac can significantly reduce postoperative pain in adults.

Postoperative pain is an aggravating problem and it is common to feel short term pain within 6 hours of surgery. Poorly managed acute postsurgery pain may profoundly impact the clinical outcomes and is a consistent risk factor for persistent or chronic postsurgery pain. Generally, nonsteroidal anti‐inflammatory drugs (NSAIDs) are administered to minimize pain. These agents work by ceasing the production of prostaglandins, or chemicals associated with pain and inflammation in the body. A significant benefit of using NSAIDs is that they can help to reduce the requirements for stronger analgesics like opioids.

Opioids are also commonly used analgesics but can lead to unwanted noxious effects like allergic reactions, nausea, vomiting, breathing problems, and constipation. Furthermore, too much opioid use might increase the drug dependence and addiction. Long term use of NSAIDs can also lead to undesirable adverse events such as potential impairment to the gut and kidneys, and bleeding at the site of the surgical wound. Thus, it is vital to weigh the risks and benefits of NSAIDs when considering them to use for promptly mitigating pain following the operation.

Among NSAIDs, Ketorolac is a widely known for its substantial analgesic potency and anti-inflammatory effects. It is known for its efficacy in treatment of moderate to severe postoperative pain following various surgeries including ENT, orthopaedic, and abdominal surgery. The literature search has shown that ketorolac is efficacious and well-tolerable in decreasing postoperative visual analogue scale (VAS) scores. It can be administered as an injection thus beneficial for patients who cannot take medicines by mouth or have difficulty in swallowing.

RATIONALE BEHIND RESEARCH

There is a paucity of studies investigating the benefits and risks of using ketorolac to improve short‐term pain after surgery. Therefore, this study was carried out.

OBJECTIVE

This systematic review was carried to investigate the pain-relieving efficacy and side effects of single‐dose ketorolac in comparison with placebo or an active comparator to treat moderate to severe post-surgery pain in adult patients.

Literature search

On 20 April 2020, databases like Embase, CENTRAL, LILACS, and MEDLINE were searched without language restrictions. For additional studies, the reference lists and clinical trials registers of retrieved articles were also explored.

Inclusion criteria

Studies were incorporated in this systematic review if:

• they were randomized, double‐blind trials
• they included a single post-surgery dose of intravenous ketorolac with placebo (a dummy treatment) or
• they included another active therapy to manage acute post-surgery pain in adults (age above 18 years) following any surgery.

Data extraction and analysis

Data related to methodology, settings, participants, interventions, context, outcomes, results, investigators and publications was collected and compared. The results of the studies were assessed and summarized. All the evidences were rated on the basis of study methodology and sizes.

Risk of Bias and Quality assessment

In this study, the standard methodological procedures expected by Cochrane was used. For subgroup assessment, the investigators planned to examine distinct doses of parenteral ketorolac separately and to examine the outcomes on the basis of the type of surgery conducted. Risk of bias assessment was conducted using risk of bias tool whereas the certainty of evidences was evaluated using Grading of Recommendation, Assessment, Development and Evaluation (GRADE).

Study outcomes

• The major endpoint was the number of people in each group attaining at least 50% pain alleviation over 4 and 6-hour periods.
• The secondary endpoints were time to and the number of people utilizing rescue medication; withdrawals due to paucity of efficacy, side effects, or due to any other cause; and the number of subjects witnessing any adverse events, serious adverse events, and NSAID or opioid‐associated adverse events.

Outcomes

Study and participant characteristics:

• Overall, 12 studies involving 1905 subjects undergoing various surgeries (orthopaedic, abdominal/pelvic, and dental), with 17 to 83 subjects receiving intravenous administration of ketorolac in each study.
• The mean age of the participants was 22.5 to 67.4 years.
• In most of the included studies, a 30 mg dose of ketorolac was administered. One study evaluated 15 mg, and another study evaluated 60 mg dose of ketorolac.
• The studies explored the management of pain after surgery on the muscles, pelvis, abdomen, teeth, joints, and bones.

Study quality:

• For most of the incorporated studies, the risk of bias was not clear for some domains, specifically allocation blinding and concealment.
• Due to the small sample size, an elevated risk of bias was noted.
• For each outcome, the overall certainty of the evidence was reported to range from very low- moderate. Imprecision, serious study limitations, and inconsistency were the reasons for downgrading certainty.

Effect of intervention on the outcome:

1) Pain reduction

A significant number of patients reported 50% pain reduction or more within 6 hrs of surgery with ketorolac, which was about three times more than placebo.

2) Need for rescue medications

The need of rescue medication was reduced in ketorolac group compared to placebo or other NSAIDs, however the evidence were not robust enough to suggest if few people need rescue medicines when treated with ketorolac.

3) Adverse events

No significant differences were observed in the number of serious adverse events between ketorolac and placebo or other NSAIDS.

The findings of this study showed the efficacy of single-dose of intravenously administered NSAID ketorolac in management of acute postoperative pain in adults. Very low‐certainty evidence from 8 studies (658 people) indicated that ketorolac considerably increases the number of people attaining at least 50% pain decline over 4 hours in comparison with placebo. However, the evidence is not very certain (RR 2.81). The number needed to treat for one additional participant to benefit (NNTB) was found to be 2.4.  Low‐certainty evidence from ten studies (914 people) demonstrates that ketorolac may remarkably raise the number of people attaining at least 50% pain improvement over 6 hours in comparison with placebo (RR 3.26). The NNTB was found to be 2.5.

However, there were no significant differences observed in number of people attaining at least 50% pain alleviation between ketorolac and other NSAIDs (low‐certainty and moderate‐certainty evidence, respectively) over both 4 and 6 hours. In four studies, ketorolac was compared to parecoxib and in two studies ketorolac was compared to diclofenac. Over 4 hours, 4 studies (337 people) produced an RR of 1.04 and over 6 hours, 6 studies (603 people) produced an RR of 1.06.

For time to rescue medication, moderate‐certainty evidence illustrated a mean median of 271 minutes for the ketorolac recipients versus 104 minutes for placebo recipients (6 studies, 633 people). For the number of people using rescue medication, very low‐certainty evidence from 5 studies (417 people) compared ketorolac with placebo. The RR was 0.60, indicating no profound differences between the groups.

Considering the time to rescue medication, low‐certainty evidence from 4 studies (427 people) indicated that people receiving ketorolac waited an additional 35 minutes. Considering the number of people using rescue medication, very low‐certainty evidence from 3 studies (260 people) investigated ketorolac vs. another NSAID. The RR was found to be 0.90, which suggests negligible differences between the groups.

Moderate‐certainty evidence revealed that ketorolac might slightly elevate the total adverse event rates in comparison with another NSAID (76% vs 68%, 5 studies, 516 participants; NNTH 12.5). The incidence of serious adverse events was rare. Low‐certainty evidence from 5 studies (530 people) did not show any difference among the adverse events between ketorolac and another NSAID. Only 1 of the 5 studies reported a single serious adverse event.

In comparison to placebo, a slight increase was observed in the rate of total adverse event rates in patients administered with ketorolac compared to placebo. Serious adverse events were noted to be rare. Low‐certainty evidence from 8 studies (703 people) did not show noteworthy differences in the rates between placebo and ketorolac. In 4 studies, ketorolac was compared to parecoxib, and in 2 studies, ketorolac was compared to diclofenac.

The certainty and amount of evidence for using ketorolac as a therapy for post-surgery pain vary across safety and efficacy outcomes and among comparators, from moderate to very low. Little to no difference might exist between ketorolac and other anti‐inflammatory agents in the number of patients whose pain is decreased by half or more. Unwanted side effects seem to occur at a slightly greater rate with ketorolac when compared to placebo and other anti‐inflammatory NSAIDs. There is a paucity of sufficient information for determining if intravenous ketorolac has a different rate of cardiovascular events, gastrointestinal or surgical‐site bleeding, or kidney dysfunction when compared to other NSAIDs. Also, there was insufficient studies in cardiovascular operations and in elderly people who might be at elevated risk of noxious effects.

Nevertheless, the findings of the study indicated that administration of ketorolac might lower short term pain following surgery by 50% (half) or more when compared to a placebo (a dummy treatment). However, additional investigations might influence this estimate and more robust evidence are needed to establish if it leads to severe unwanted effects.