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