This is an updated version of the original Cochrane review published in Issue 10, 2011. Paracetamol (acetaminophen) is the most commonly prescribed analgesic for the treatment of acute pain. It may be administered orally, rectally, or intravenously. The efficacy and safety of intravenous (IV) formulations of paracetamol, IV paracetamol, and IV propacetamol (a prodrug that is metabolized to paracetamol), compared with placebo and other analgesics, is unclear.
To assess the efficacy and safety of IV formulations of paracetamol for the treatment of postoperative pain in both adults and children.
We ran the search for the previous review in May 2010. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE (May 2010 to 16 February 2016), EMBASE (May 2010 to 16 February 2016), LILACS (2010 to 2016), a clinical trials registry, and reference lists of reviews for randomized controlled trials (RCTs) in any language and we retrieved articles.
Randomized, double‐blind, placebo‐ or active‐controlled single dose clinical trials of IV paracetamol or IV propacetamol for acute postoperative pain in adults or children.
Data collection and analysis
Two review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We contacted study authors for additional information. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence.
We included 75 studies (36 from the original review and 39 from our updated review) enrolling a total of 7200 participants.
Among primary outcomes, 36% of participants receiving IV paracetamol/propacetamol experienced at least 50% pain relief over four hours compared with 16% of those receiving placebo (number needed to treat to benefit (NNT) = 5; 95% confidence interval (CI) 3.7 to 5.6, high quality evidence). The proportion of participants in IV paracetamol/propacetamol groups experiencing at least 50% pain relief diminished over six hours, as reflected in a higher NNT of 6 (4.6 to 7.1, moderate quality evidence). Mean pain intensity at four hours was similar when comparing IV paracetamol and placebo, but was seven points lower on a 0 to 100 visual analog scale (0 = no pain, 100 = worst pain imaginable, 95% CI ‐9 to ‐6, low quality evidence) in those receiving paracetamol at six hours.
For secondary outcomes, participants receiving IV paracetamol/propacetamol required 26% less opioid over four hours and 16% less over six hours (moderate quality evidence) than those receiving placebo. However, this did not translate to a clinically meaningful reduction in opioid‐induced adverse events.
Meta‐analysis of efficacy comparisons between IV paracetamol/propacetamol and active comparators (e.g., opioids or nonsteroidal anti‐inflammatory drugs) were either not statistically significant, not clinically significant, or both.
Adverse events occurred at similar rates with IV paracetamol or IV propacetamol and placebo. However, pain on infusion occurred more frequently in those receiving IV propacetamol versus placebo (23% versus 1%). Meta‐analysis did not demonstrate clinically meaningful differences between IV paracetamol/propacetamol and active comparators for any adverse event.
Since the last version of this review, we have found 39 new studies providing additional information. Most included studies evaluated adults only. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides high quality evidence that a single dose of either IV paracetamol or IV propacetamol provides around four hours of effective analgesia for about 36% of patients with acute postoperative pain. Low to very low quality evidence demonstrates that both formulations are associated with few adverse events, although patients receiving IV propacetamol have a higher incidence of pain on infusion than both placebo and IV paracetamol.
Ewan D McNicol, McKenzie C Ferguson, Simon Haroutounian, Daniel B Carr, Roman Schumann
Plain language summary
Intravenous paracetamol (acetaminophen) for pain after surgery in adults and children
Pain is commonly experienced after surgical procedures and multiple medications (e.g., painkillers) are routinely used to control it. In February 2016, we searched for clinical trials looking at intravenous (IV) formulations (solutions that can be administered directly into a vein) of paracetamol (either IV paracetamol or IV propacetamol) and how they might manage pain after surgery.
Results and quality of the evidence
Our updated review included data from 75 studies of 7200 patients with moderate‐to‐severe pain after an operation. We found high quality evidence that IV paracetamol or IV propacetamol provided pain relief for four hours for about 36% of people versus 16% of those receiving placebo. Direct comparisons with other painkillers, such as morphine and anti‐inflammatories, did not show large differences (if any) in effectiveness, although this may have been due to the small numbers of patients studied.
Low quality evidence showed that IV paracetamol and IV propacetamol produced few side effects. However, patients receiving IV propacetamol complained of pain at the site their medication was infused at more often than those receiving placebo or IV paracetamol.
Due to the amount of data already included in our review, we think it is unlikely that any new studies will change our conclusions. However, we found very few studies that included children, so this is an area that requires further investigation.
Ewan D McNicol, McKenzie C Ferguson, Simon Haroutounian, Daniel B Carr, Roman Schumann
Implications for practice
We identified a large amount of additional data for this update; however our original conclusions remain largely unchanged.
For people with postoperative pain
Data of various quality demonstrate that a higher number of patients have clinically meaningful pain relief and that more patients are satisfied with treatment versus placebo. Patients should expect pain relief to be superior to that achieved with placebo, with a similar degree of side effects. Most patients will receive intravenous (IV) paracetamol or IV propacetamol as part of a multi‐modal pain regimen.
Our meta‐analysis includes high to very low quality evidence that IV paracetamol and IV propacetamol provide superior analgesia in comparison to placebo. Neither IV paracetamol nor IV propacetamol were clinically superior for any efficacy outcome versus other analgesic agents, such as nonsteroidal anti‐inflammatory drugs (NSAIDs) or opioids. Given alone, they are unlikely to provide sufficient analgesia after surgeries that produce moderate‐to‐severe pain. If used in combination with opioids they reduce opioid consumption, but this reduction does not appear sufficient to reduce opioid‐induced adverse effects (AEs). Both offer an advantage over oral paracetamol due to their faster onset of action and in that many patients are unable to tolerate oral medication postsurgically. Intravenous paracetamol may prove a better option versus IV propacetamol as reconstitution is not required and because the incidence of pain on infusion is reduced.
For policy makers
The availability of either IV paracetamol or IV propacetamol varies by country. The decision to add either formulation to a hospital formulary should take into account how adding one would affect current policies for analgesic algorithms, additional workload, and patient satisfaction.
The cost of IV paracetamol and IV propacetamol also varies by country. In the United States, IV paracetamol is considerably more expensive than either the oral formulation or than parenteral formulations of other analgesics. There are few studies comparing oral versus parenteral formulations of paracetamol; however, given the postoperative setting, the utility of orally administered analgesia may be limited. Our findings do not demonstrate superiority in efficacy or safety of IV paracetamol versus other analgesics that would justify increased cost. However, given that hospital reimbursement is, in part, contingent on patient satisfaction data in some countries, increases in direct costs may be offset by such policies.
Implications for research
More studies that assess self reported pain in pediatric patients are required. Self report pain assessment tools such as the Faces Pain Scale and the Color Analog Scale are validated for use in children as young as three years of age.
Our analyses, based on limited evidence, suggest that IV propacetamol or IV paracetamol reduce opioid consumption, but not to a sufficient degree to reduce opioid‐induced AEs. Larger trials that accurately and prospectively assess adverse events, and that are sufficiently powered to demonstrate a difference, are required to confirm or contradict this finding. Many of the included studies may have been underpowered to show a difference between interventions where one actually exists.
Few included studies reported power calculations ‐ future studies should include them. One of the included studies tested a dose of 2 g of IV paracetamol and demonstrated superior analgesic efficacy versus 1 g (Juhl 2006). Further studies at this higher dose may provide evidence that IV paracetamol reduces opioid consumption to an extent that opioid‐induced AEs are reduced. Equally, they may show an increase in paracetamol‐induced AEs.Get full text at The Cochrane Library
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