Single‐dose intravenous diclofenac for acute postoperative pain in adults Stable (no update expected for reasons given in 'What's new')

Abstract

Abstract Background

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

Objectives

To assess the analgesic efficacy and adverse effects of single‐dose intravenous diclofenac, 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: the Cochrane Central Register of Controlled Trials (Cochrane Register of Studies Online), MEDLINE, and Embase on 22 May 2018. 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 diclofenac 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 four‐ and six‐hour period.

Our secondary outcomes were time to, and number of participants using rescue medication; withdrawals due to lack of efficacy, AEs, and for any cause; and number of participants experiencing any AE, serious AEs (SAEs), and NSAID‐related AEs. We performed a post hoc analysis of opioid‐related AEs, to enable indirect comparisons with other analyses of postoperative analgesics.

For subgroup analysis, we planned to analyze different doses and formulations of parenteral diclofenac separately.

We assessed the overall quality of the evidence for each outcome using GRADE and created two 'Summary of findings' tables.

Main results

We included eight studies, involving 1756 participants undergoing various surgeries (dental, mixed minor, abdominal, and orthopedic), with 20 to 175 participants receiving intravenous diclofenac in each study. Mean study population ages ranged from 24.5 years to 54.5 years. Intravenous diclofenac doses varied among and within studies, ranging from 3.75 mg to 75 mg. Five studies assessed newer formulations of parenteral diclofenac that could be administered as an undiluted intravenous bolus. Most studies had an unclear risk of bias for several domains and a high risk of bias due to small sample size. The overall quality of evidence for each outcome was generally low for reasons including unclear risk of bias in studies, imprecision, and low event numbers.

Primary outcome 

Three studies (277 participants) produced a number needed to treat for an additional beneficial outcome (NNTB) for at least 50% of maximum pain relief versus placebo of 2.4 (95% confidence interval (CI) 1.9 to 3.1) over four hours (low‐quality evidence). Four studies (436 participants) produced an NNTB of 3.8 versus placebo (95% CI 2.9 to 5.9) over six hours (low‐quality evidence). No studies provided data for the comparison of intravenous diclofenac with another NSAID over four hours. At six hours there was no difference between intravenous diclofenac and another NSAID (low‐quality evidence).

Secondary outcomes 

For secondary efficacy outcomes, intravenous diclofenac was generally superior to placebo and similar to other NSAIDs.

For time to rescue medication, comparison of intravenous diclofenac versus placebo demonstrated a median of 226 minutes for diclofenac versus 80 minutes for placebo (5 studies, 542 participants, low‐quality evidence). There were insufficient data for pooled analysis for comparisons of diclofenac with another NSAID (very low‐quality evidence).

For the number of participants using rescue medication, two studies (235 participants) compared diclofenac with placebo. The number needed to treat to prevent one additional harmful event (NNTp) (here, the need for rescue medication) compared with placebo was 3.0 (2.2 to 4.5, low‐quality evidence). The comparison of diclofenac with another NSAID included only one study (98 participants). The NNTp was 4.5 (2.5 to 33) for ketorolac versus diclofenac (very low‐quality evidence).

The numbers of participants withdrawing were generally low and inconsistently reported (very low‐quality evidence). Participant withdrawals were: 6% (8/140) diclofenac versus 5% (7/128) placebo, and 9% (8/87) diclofenac versus 7% (6/82) another NSAID for lack of efficacy; 2% (4/211) diclofenac versus 0% (0/198) placebo, and 3% (4/138) diclofenac versus 2% (2/129) another NSAID due to AEs; and 11% (21/191) diclofenac versus 17% (30/179) placebo, and 18% (21/118) diclofenac versus 15% (17/111) another NSAID for any cause.

Overall adverse event rates were similar between intravenous diclofenac and placebo (71% in both groups, 2 studies, 296 participants) and between intravenous diclofenac and another NSAID (55% and 58%, respectively, 2 studies, 265 participants) (low‐quality evidence for both comparisons). Serious and specific AEs were rare, preventing meta‐analysis.

There were sufficient data for a dose‐effect analysis for our primary outcome for only one alternative dose, 18.75 mg. Analysis of the highest dose employed in each study demonstrated a relative benefit compared with placebo of 1.9 (1.4 to 2.4), whereas for the group receiving 18.75 mg, the relative benefit versus placebo was 1.6 (1.2 to 2.1, 2 studies). Compared to another NSAID, the high‐dose analysis demonstrated a relative benefit of 0.9 (0.8 to 1.1), for the group receiving 18.75 mg, the relative benefit was 0.78 (0.65 to 0.93). For direct comparison of high dose versus 18.75 mg, the proportion of participants with at least 50% pain relief was 66% (90/137) for the high‐dose arm versus 57% (77/135) in the low‐dose arm. There were insufficient data for subgroup meta‐analysis of different diclofenac formulations.

Authors' conclusions

The amount and quality of evidence for the use of intravenous diclofenac as a treatment for postoperative pain is low. The available evidence indicates that postoperative intravenous diclofenac administration offers good pain relief for the majority of patients, but further research may impact this estimate. Adverse events appear to occur at a similar rate to other NSAIDs. Insufficient information is available to assess whether intravenous diclofenac has a different rate of bleeding, renal dysfunction, or cardiovascular events versus other NSAIDs. There was insufficient information to evaluate the efficacy and safety of newer versus traditional formulations of intravenous diclofenac. There was a lack of studies in major and cardiovascular surgeries and in elderly populations, which may be at increased risk for adverse events.

Author(s)

Ewan D McNicol, McKenzie C Ferguson, Roman Schumann

Abstract

Plain language summary

Single‐dose intravenous diclofenac for short‐term pain after surgery in adults 

Bottom line 

There is some evidence that intravenous diclofenac is effective for reducing pain after surgery in adults, but it is less clear how safe it is in this setting.

Background 

Pain is common in the short term after surgery. Non‐steroidal anti‐inflammatory drugs (NSAIDs, aspirin‐like drugs) are often given along with opioids (such as morphine) to treat pain. However, NSAIDs may cause bleeding (e.g. at the site of an incision or wound) and injury to the kidneys and gut. Diclofenac is an NSAID that can be given by injection into a vein (intravenously), which may be useful when patients are not able to take medicines by mouth.

Study characteristics 

In May 2018, we searched for clinical trials where intravenous diclofenac was used to treat pain after surgery in adults. We found eight studies enrolling a total of 1756 people that met our requirements. The studies were similar in their design, although they were carried out in different surgeries (dental, mixed minor surgeries, abdominal, and orthopedic). The dose of intravenous diclofenac used also varied. Intravenous diclofenac was mostly compared to placebo (a sham treatment, such as a bag of saline administered into a vein) or another NSAID.

Key findings 

We were most interested in determining the number of participants with at least half the maximum possible pain relief over four or six hours after treatment. Around twice as many participants had at least half the maximum possible pain relief when they received diclofenac versus those who received placebo. When diclofenac was compared with another NSAID, similar numbers of participants had at least half the maximum possible pain relief. Other assessments, such as how quickly and how many participants needed rescue medication (an extra pain medication available to study participants if the study medication is not treating the participant's pain well enough), and how many participants withdrew from a study, also usually showed that intravenous diclofenac was better than placebo and similar to other NSAIDs.

There was insufficient information in the studies to make a good assessment of side effects and serious side effects, but the rate at which they occurred appeared to be similar among all treatments. Very few participants dropped out of the studies because of side effects. This is usually the case in studies where patients are only in a study for a short period of time.

Quality of the evidence 

We generally rated the quality of the evidence for each assessment as low due to issues with the design of many of the studies, and low overall numbers of people enrolled. Low‐quality evidence means that further research may have an important impact on our findings.

Author(s)

Ewan D McNicol, McKenzie C Ferguson, Roman Schumann

Reviewer's Conclusions

Authors' conclusions

Implications for practice For adults with moderate to severe postoperative pain

The amount and quality of evidence for the use of diclofenac for treating postoperative pain is low. The evidence we have indicates that postoperative administration of diclofenac offers good pain relief for the majority of patients, but further research may impact this estimate. Adverse events appear to occur at a similar rate to other non‐steroidal anti‐inflammatory drugs (NSAIDs), but information is insufficient to assess whether diclofenac has a different rate of bleeding, renal dysfunction, or cardiovascular events when compared with other NSAIDs. We have insufficient information to confirm that newer formulations of diclofenac are more effective and safer than traditional formulations.

For clinicians

The amount and quality of evidence for the use of diclofenac for treating postoperative pain is low. The evidence we have indicates that postoperative administration of diclofenac offers good pain relief for the majority of patients, but further research may impact this estimate. Adverse events appear to occur at a similar rate to other NSAIDs, but information is insufficient to assess whether diclofenac has a different rate of bleeding, renal dysfunction, or cardiovascular events when compared with other NSAIDs. We have insufficient information to confirm that newer formulations of diclofenac are more effective and safer than traditional formulations.

For policymakers

The amount and quality of evidence for the use of diclofenac for treating postoperative pain in is low, and policymakers should exercise caution when recommending its use in postoperative guidelines. The evidence we have indicates that postoperative administration of diclofenac offers good pain relief for the majority of patients, but further research may impact this estimate. Adverse events appear to occur at a similar rate to other NSAIDs, but information is insufficient to assess whether diclofenac has a lower rate of bleeding, renal dysfunction, or cardiovascular events when compared with other NSAIDs. We have insufficient information to confirm that newer formulations of diclofenac are more effective and safer than traditional formulations.

For funders

The amount and quality of evidence for the use of diclofenac for treating postoperative pain is low. The evidence we have indicates that postoperative administration of diclofenac offers good pain relief for the majority of patients, but further research may impact this estimate. Adverse events appear to occur at a similar rate to other NSAIDs, but information is insufficient to assess whether diclofenac has a lower rate of bleeding, renal dysfunction, or cardiovascular events when compared with other NSAIDs. We also have insufficient information to confirm that newer, more expensive formulations of diclofenac are more effective and safer than traditional formulations, or that any potential differences in efficacy (pain relief, time to onset of analgesia, requirement for rescue analgesia), safety (rate of thrombophlebitis), or administration costs (no requirement for dilution, quicker administration) translate to a lower overall cost of therapy. Similarly, it is unclear whether the increased cost of parenteral formulations of diclofenac versus oral formulations is offset by increased effectiveness and reduced overall costs.

Implications for research General

While more studies are required to be able to more accurately estimate efficacy and safety of parenteral diclofenac, there is a lack of studies specifically in major and cardiovascular surgeries and in elderly populations.

Design

The studies included in our review were designed to detect differences in efficacy between interventions. However, further studies that compare different doses of diclofenac may establish whether doses lower than those currently employed are equally effective. Serious adverse events and adverse events associated with NSAIDs were rare or very rare. Epidemiological studies may more accurately determine the adverse profile of diclofenac in this setting.

Outcomes

Endpoints and the pain scoring scales used to assess them in these studies have been extensively validated. The majority of studies assessed pain relief after administration of each intervention, an outcome shown to be clinically important to patients. While the cost of newer formulations of parenteral diclofenac varies between (and in some cases within) countries, it is typically considerably higher than older formulations or oral formulations. Studies conducting cost‐benefit analyses may determine whether this increased cost is offset by increased effectiveness and reduced overall costs.

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