REVIEW ARTICLE
Single-dose Systemic Acetaminophen to Prevent Postoperative Pain A Meta-analysis of Randomized Controlled Trials Gildasio S. De Oliveira, Jr, MD, MSCI, Lucas J. Castro-Alves, MD, and Robert J. McCarthy, PharmD
Objectives: The effect of a single-dose systemic acetaminophen to treat postoperative pain has been previously quantified, but the effect of systemic acetaminophen to prevent postoperative pain is currently not well defined. The preventive analgesic effect of acetaminophen has yet to be quantified in a meta-analysis. The objective of the current investigation was to evaluate the effect of a single preventive dose of systemic acetaminophen on postoperative pain outcomes. Materials and Methods: A wide search was performed to identify randomized controlled trials that evaluated the effects of a single dose of systemic acetaminophen on pain outcomes in a large variety of surgical procedures. Meta-analysis was performed using a random-effect model. Results: Eleven randomized clinical trials evaluating 740 patients were included in the analysis. The weighted mean difference (95% confidence interval [CI]) of the combined effects favored acetaminophen over control for early pain at rest (r4 h, 1.1 ( 2.0 to 0.2)) and early pain at movement (24 h, 1.9 ( 2.8 to 1.0)) Postoperative opioid consumption was decreased in the systemic acetaminophen group compared with control. Weighted mean difference (95% CI) of 9.7 ( 13.0 to 6.4) mg morphine intravenous equivalents systemic acetaminophen also reduced postoperative nausea and vomiting compared with control, odds ratio (95% CI) of 0.25 (0.13 to 0.47), numbers needed to treat (95% CI) = 3.3 (2.3 to 5.9).
modalities can result in better postoperative pain control for surgical patients.4,5 However, phramacological interventions that are effective to treat postoperative pain may not have the same efficacy when examined as a preventive analgesic strategy.6,7 In addition, the fast hospital discharge of ambulatory patients or undesirable side effects may only allow a single-dose administration of a systemic analgesic drug.8–10 Systemic acetaminophen has been used in Europe for many years but only recently it became available in the United States. Several clinical studies have examined the use of systemic acetaminophen in the perioperative setting with varying results. In addition, previous quantitative systematic reviews did not differentiate between a preventive versus a treatment effect of the drug.11,12 It is, therefore, unknown if systemic acetaminophen, when given as single dose, is an effective strategy to prevent postsurgical pain. The main objective of the current investigation was to examine the effect of systemic acetaminophen on postoperative pain outcomes when the drug was given as a preventive analgesic strategy. We also sought to investigate a possible association between acetaminophen dosage and drug effects on postoperative pain outcomes.
Discussion: Systemic acetaminophen, when used as a single-dose preventive regimen, is an effective intervention to reduce postoperative pain. It also reduces postoperative nausea and/or vomiting. Doses >1 g were not associated with greater reduction in pain outcomes.
We performed a quantitative systematic review following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.13
Key Words: acetaminophen, pain, preventive, surgery
Systematic Search
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mprovement of postoperative pain outcomes seems to be an important pathway to ameliorate patients’ quality of postsurgical recovery.1–3 The use of preventive analgesic
Received for publication November 1, 2013; revised February 25, 2014; accepted January 27, 2014. From the Department of Anesthesiology, Northwestern University, Chicago, IL. Supported by Department of Anesthesiology, Northwestern University, Chicago, IL. Dr De Oliveira has received a research Grant from Cadence Pharmaceuticals. Cadence pharmaceuticals was not involved in any aspect in the study. The other authors declare no conflict of interest. Reprints: Gildasio S. De Oliveira Jr, MD, MSCI, Department of Anesthesiology, Northwestern University, 241 East Huron St F5704, 60611 Chicago, IL (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins DOI: 10.1097/AJP.0000000000000081
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MATERIALS AND METHODS
Published reports of randomized trials evaluating the effects of intravenous acetaminophen on surgical postoperative pain were searched using the National Library of Medicine’s PubMed database, the Cochrane Database of Systematic Reviews and Google Scholar inclusive to July 1, 2013. Free text and MeSH terms “acetaminophen,” “propacetamol,” “paracetamol,” “pain,” “preoperative,” “analgesia,” “surgery,” and “opioid” were used individually and in pairwise combinations. No language restriction was used. An attempt to identify additional studies not found by the primary search methods was made by reviewing the reference lists from identified studies. No search was performed for unpublished studies. This initial search yielded 491 manuscripts.
Selection of Included Studies The study’s inclusion and exclusion criteria were determined before the systematic search. Two authors (G.S.D.O. and L.J.C.A.) independently evaluated the abstract and results of the 491 articles obtained by the Clin J Pain
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initial search. Articles that were clearly not relevant based on our inclusion and exclusion criteria were excluded at this phase. Disagreements on inclusion of the articles were resolved by discussion among the evaluators. If an agreement could not be reached, the dispute was resolved with the help of a third investigator (R.J.M,). The third investigator was blinded regarding evaluation of the first 2 authors.
Inclusion and Exclusion Criteria We included randomized controlled trials that compared a single-dose intravenous acetaminophen preoperative or intraoperative with an inactive (placebo or “no treatment”) control group in patients undergoing surgical procedures. Studies containing a concurrent use of an alternative multimodal analgesia regimen were excluded if a direct comparison of acetaminophen and control could not be established. Comparisons that examined acetaminophen for treatment of postoperative pain but not for prevention (preoperative or intraoperative administration) were also excluded. Included studies had to report at least on pain scores or opioid consumption as postoperative pain outcomes. No minimum sample size was required for inclusion in the meta-analysis.
Validity Scoring Two authors (G.S.D.O. and L.J.C.A.) independently read the included reports and assessed their methodological validity using a modified Jadad 5-point quality scale.14 The scale evaluates the study for the following: randomization, double-blind evaluation, concealment of study group to evaluator, valid randomization method, and completeness of data at follow-up.
Data Extraction Two authors (G.S.D.O. and L.J.C.A.) independently evaluated the full manuscripts of all included trials and performed data extraction using a data collection form specifically developed for this review. Data extracted from trials included the acetaminophen dose, time of drug administration (preoperatively or intraoperatively at the end of surgery), sample size, number of patients in treatment groups, follow-up period, type of surgery, early pain scores (r4 h) at rest and at movement, late pain scores (24 h) at rest and at movement, cumulative opioid consumption, time to rescue analgesic administration (min), and adverse events. Postoperative opioid consumption was converted to the equivalent dose of intravenous morphine.15 Visual analog scale of pain were converted to a 010 numeric rating scale. Data presented only as median and range was converted to means and SD using previously described methodology.16
Single-dose Systemic Acetaminophen
Meta-Analysis The weighted mean differences (WMDs) with 95% confidence interval (CI) were determined and reported for continuous data. For dichotomous data (adverse effects), the Peto odds ratio (OR) (to account for the potential of zero counts in the cells for low-frequency outcomes) and 95% CI are reported. For primary outcomes, a significant effect compared with placebo required that the 95% CI for continuous data did not include zero and for dichotomous secondary data, the 95% confidence interval did not include 1.0. Because of the different surgical procedures, we used a random-effect model in an attempt to generalize our findings to studies not included in our meta-analysis.17 Publication bias was evaluated by examining for asymmetric funnel plots using Egger and colleague’s regression test.18,19 A file drawer analysis described by Rosenthal20 was performed in the case of an asymmetric funnel plot. The conversion of propacetamol to paracetamol was performed using a 2:1 ratio as previously recommended.21 Heterogeneity of the included studies was further evaluated if the I2 statistic was >50%. Further analysis was planned a priori to explore nontrivial heterogeneity of the treatment effect across the included studies including time of drug administration (preoperatively vs. intraoperatively at the end of surgery) and quality of included studies evaluated by the Jadad score. The proportion of the total variance explained by the covariates (R2) was calculated by dividing the random-effects pooled estimates of variance (t2) within studies by the total variance (total t2). The value obtained was then subtracted from 1. When values fall outside the range of 0% to 100%, they were set to the closest value (0% or 100%). A meta-regression analysis was performed to evaluate a possible association between total acetaminophen dose and the effect size on evaluated outcomes.22 In studies that reported a weight-based dosage, the total value was obtained using the mean reported weight. In cases that weight was not reported, 70 kg was used a reference value. Analysis was performed using Stata version 13 (College Station, TX) and Comprehensive Meta-analysis software version 2 (Biostat, Englewood, NJ).
RESULTS
Early acute postoperative pain scores (visual analog scale) at rest and at movement (0 to 4 h postoperatively; late acute postoperative pain scores (visual analog scale) at rest and at movement (24 h postoperatively); and cumulative opioid consumption (24 h) in the postoperative period.
Of the initially evaluated abstracts, 30 studies initially met the inclusion criteria (Fig. 1). Nineteen studies were subsequently excluded: 6 studies did not report on evaluated outcomes or comparisons,23–28 1 study was not performed in humans,29 2 manuscripts were not randomized trials,30,31 2 evaluated children,32,33 3 did not provide a direct comparison between systemic acetaminophen and control,34–36 and 5 evaluated multiple doses.37–41 The characteristics of the 11 included studies are listed in Table 1. The evaluated trials included data from 740 patients and were published between 2003 and 2013.42–52 The median and interquartile range number of patients of the included studies receiving IV acetaminophen was 36 (28 to 50). The median and interquartile range of the modified Jadad scale score was 4 (3 to 5). All 11 studies reported on opioid consumption and/or pain scores. Three studies reported pain scores for both rest and activity.45,49,52
Secondary Outcomes
Early (0 to 4 h) Pain at Rest
The time to first analgesic administration (min); adverse events including: pruritus, postoperative nausea, and/or vomiting.
The aggregate effect of the 9 studies (13 comparisons) evaluating the effect of systemic acetaminophen on early pain at rest favored acetaminophen over control with a
Definition of Relevant Outcome Data Primary Outcomes
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compared with control did not reveal a benefit in relation to a large confidence interval, WMD (95% CI) of 0.4 ( 0.9 to 0.05) (0-10 numerical scale). Heterogeneity was high (I2 = 72%). The variance was not altered by time of drug administration (preoperatively vs. postoperatively). In contrast, 100% of the heterogeneity could be explained by lower quality studies (Jadadr3) with low heterogenity among higher quality studies (I2 = 0).
Late Pain (24 h) at Movement Only 2 studies examined the effect of systemic acetaminophen on late pain at movement compared with control. The study of Moon et al45 did not reveal a significant effect in relation to a large confidence interval, WMD (95% CI) of 0.2( 1.1 to 0.7) (0-10 numerical scale). In contrast, the study of Arici et al49 showed a significant effect of acetaminophen on late pain at movement when compared with control, WMD (95% CI) of 2.7 ( 3.6 to 1.7).
Postoperative Opioid Consumption (up to 24 h)
FIGURE 1. Flowchart outlining retrieved, excluded, and evaluated randomized controlled trials.
WMD (95% CI) of 1.1 ( 2.0 to 0.2).45–52 (0-10 numerical scale) (Fig. 2). Three studies provided >1 independent comparisons that were included in the analysis.48,49,52 There was no evidence of publication bias as given by the test for an asymmetric funnel plot (P = 0.21). Heterogeneity was high (I2 = 87) but it could be explained by the by time of drug administration (preoperatively vs. postoperatively) with a low heterogeneity when the drug was administered preoperatively (I2 = 19). A meta-regression analysis did not identify an association between the acetaminophen dose administered and an effect on early pain at rest (Slope (95% CI) = 0.4 ( 0.89 to 1.70), P = 0.53 compared with slope = 0).
The aggregated effect of 9 studies (14 comparisons)42–45,47–49,51,52 evaluating the effect of systemic acetaminophen on postoperative opioid consumption compared with control favored acetaminophen, WMD (95% CI) of 9.7 ( 13.0 to 6.4) mg morphine intravenous equivalents (Fig. 4). Four studies provided >1 independent comparisons that were included in the analysis.42,48,49,52 The funnel plot demonstrated asymmetry (P = 0.02) suggesting the possibility of publication bias. It would be required to detect 14 missing negative studies to significantly change the analysis. Heterogeneity was high (I2 = 97%) and it could not be explained by time of the drug administration (preoperatively vs. postoperatively). In contrast, 36% of the total variance could be explained by the inclusion of lower quality studies (Jadadr3). The opioid-sparing effect was greater when preventive acetaminophen was given for patients undergoing procedures with general anesthesia, WMD (95% CI) of 13.2( 18.5 to 7.8) mg of IV morphine equivalents compared with 3.1 ( 5.2 to 0.9) mg of IV morphine equivalents when acetaminophen was given to patients undergoing regional/local anesthesia, P = 0.006. A metaregression analysis did not suggest an association between the acetaminophen dose administered and the effect on postoperative opioid consumption (Slope (95% CI) = 4.6 ( 1.3 to 10.7), P = 0.12 compared with slope = 0).
Time to First Analgesic Administration (min) Early (0 to 4 h) Pain at Movement The overall effect of 3 studies (6 comparisons)45,49,52 evaluating the effect of systemic acetaminophen on early pain at movement compared with control favored acetaminophen, WMD (95% CI) of 1.9 ( 2.8 to 1.0) (0-10 numerical scale) (Fig. 3) Two studies provided >1 independent comparisons that were included in the analysis.49,52 Egger and colleague’s regression suggested the possibility of publication bias (P = 0.047). Rosenthal and colleagues’ analysis revealed that 6 additional negative studies would be required to change the results. Heterogeneity was high (I2 = 70) and it could be explained 100% by the preoperative administration of the drug.
Late (24 h) Pain at Rest The overall effect of 5 studies (7 comparisons)42,44–46,49 examining systemic acetaminophen on late pain at rest
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Six studies (8 comparisons) evaluating the effect of systemic acetaminophen on time to first analgesic administration demonstrated a significant effect compared with control, WMD (95% CI) of 14.9 (7.2 to 22.6) minutes.42–44,47–49 Two studies reported >1 independent comparisons that were included in the analysis.42,48 The funnel plot was not asymmetric (P = 0.07). Heterogeneity was high (I2 = 95%) and it could not be explained by the time of drug administration or the quality of included studies.
Safety Analysis Postoperative Nausea and/or Vomiting The aggregated effect of 3 studies (4 comparisons) of systemic acetaminophen on postoperative nausea and/or vomiting favored acetaminophen compared with placebo, OR (95% CI) of 0.25 (0.13 to 0.47),44,45,49 numbers needed r
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Single-dose Systemic Acetaminophen
TABLE 1. Summary of Studies Included in Analysis
References Khalili et al42
Procedures Lower extremity orthopedic
Olonisakin Gynecologic surgery et al43
Number Treatment/ Control 50/25
28/28
Arslan et al44
Thyroidectomy
30/30
Moon et al45
Hysterectomy
36/35
Sen et al46
Hand surgery
20/20
Salihoglu et al47
Laparoscopic cholecystectomy
20/20
Salonen et al48
Tonsillectomy
76/38
Arici et al49 Abdominal hysterectomy
55/27
Api et al50
Curretage
36/34
Silvanto et al51
Tonsillectomy
35/36
Hahn et al52
Laparoscopic tubal ligation
45/16
Treatment
Type of Anesthesia
Acetaminophen Spinal 0.5% 15 mg/kg before bupivacaine beginning of surgery or Acetaminophen 15 mg/kg at the end of surgery Acetaminophen 1 g Not at the end of standardized surgery Acetaminophen 1 g Thiopental/ at the end of fentanyl/ surgery isofurane/ nitrous oxide Acetaminophen 2 g Propofol/ before beginning fentanyl/ of surgery sevofurane/ nitrous oxide Acetaminophen IV regional 300 mg before block with beginning of lidocaine surgery Acetaminophen 1 g Propofol/ before beginning remifentaof surgery nil/ desflurane Acetaminophen 1 g Propofol/ or 2 g at the end fentanyl/ of surgery sevoflurane/ nitrous oxide Acetaminophen 1 g Propofol/ before beginning fentanyl/ or sevoflurane/ Acetaminophen 1 g nitrous at the end of oxide surgery Acetaminophen 1 g Not before beginning standardized of surgery Acetaminophen 3 g Local before beginning infiltration of surgery with lidocaine Acetaminophen Propofol/ 1.4 g or 0.66 g or remifentanil 0.34 g at the end of surgery
Postoperative Analgesia
Modified Jadad Method of Data Score (1-5)14 Extraction ASA Class
Meperidine 0.05 mg/kg IV
5
Text/table
I, II
Morphine 2 mg IV
3
Table/text
I, II
Tramadol IV
3
Table/text
I, II
Hydromorphone 0.2 mg PCA IV
5
Table/text/ I, II figure
Fentanyl 1 mcg/ kg IV
4
Table/text
I, II
Morphine 2 mg IV
4
Table/text
I, II
Oxycodone 2 mg IV
5
Table/text/ I, II figure
Morphine IV PCA
2
Table/text/ I, II figure
Not standardized
4
Text
Morphine IV PCA
4
Table/text/ I, II figure
Alfentanil 0.1 mg IV PCA
4
Table/text/ I, II figure
Not described
PCA indicates patient controlled analgesia.
to treat (95% CI) = 3.3 (2.3 to 5.9) (Fig. 5). One study provided >1 independent comparisons that were included in the analysis.49 There was no evidence for an asymmetric funnel plot (P = 0.48). Heterogeneity was low (I2 = 0).
0.47 (0.04 to 5.4). In contrast, the study of Araci et al49 demonstrated a reduction on the incidence of pruritus by acetaminophen, OR (95% CI) of 0.1 (0.07 to 0.65).
Major Side Effects
Pruritus
None of the included studies reported any cases of major side effects (liver damage, anaphylaxis, renal failure).
Two studies evaluated the effect of systemic acetaminophen on the incidence of postoperative pruritus. The study of Moon et al45 did not show a significant benefit of acetaminophen compared with control, OR (95% CI) of
The most important finding of the current investigation was the clinically significant effect of systemic
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DISCUSSION
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FIGURE 2. Meta-analysis evaluating the effect of a single preventive dose of systemic acetaminophen on early pain scores (r4 h) at rest compared with control. The overall effect of systemic acetaminophen versus control was estimated using a random effect. Point estimate (95% confidence interval [CI]) for overall effect was 1.1 ( 2.0 to 0.2) (0-10 numerical scale). Weighted mean difference for individual studies represented by square on Forrest plot with 95% CI of the difference shown as solid line. Larger sized square and thicker 95% CI line denote larger sample size. The diamond represents the pooled estimate and uncertainty for the effects of the systemic acetaminophen compared with control.
acetaminophen on analgesia outcomes when given as a single-dose preventive strategy. A single-dose acetaminophen promoted a large reduction in postoperative opioid consumption (approximately 10 mg IV morphine equivalents). In addition, early pain outcomes (rest and movement) were also improved postoperatively in patients who received systemic acetaminophen. Taken together, our results suggest that a single preventive dose of systemic acetaminophen is an effective intervention to mitigate postsurgical pain. Surgical procedures performed in an outpatient setting continue to grow around the world.53,54 The fast discharge of ambulatory patients or the fear for potential side effects may only allow a single dose of systemic acetaminophen to be administered. Our current results support the preventive
use of acetaminophen as an effective intervention in those circumstances. Another important finding of the current investigation was the reduction of postoperative nausea and/or vomiting in patients who received a single-dose systemic acetaminophen compared with control. The effect was comparable with other commonly used antiemetics.55,56 It is not unusual for established perioperative pain interventions to be unable to demonstrate benefits on opioid-related side effects and other recovery measures.57–59 Apfel et al60 has recently demonstrated the benefit of acetaminophen to prevent postoperative nausea and vomiting (PONV) but the authors did not discriminate in regards to number of dosages and treatment versus preventive strategy. Our current results extend the findings of Apfel and colleagues on the
FIGURE 3. Meta-analysis evaluating the effect of a single preventive dose of systemic acetaminophen on early pain scores (r4 h) at movement compared with control. The overall effect of systemic acetaminophen versus control was estimated using a random effect. Point estimate (95% confidence interval [CI]) for overall effect was 1.9 ( 2.8 to 1.0) (0-10 numerical scale). Weighted mean difference for individual studies represented by square on Forrest plot with 95% CI of the difference shown as solid line. Larger sized square and thicker 95% CI line denote larger sample size. The diamond represents the pooled estimate and uncertainty for the effects of the systemic acetaminophen compared with control.
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Single-dose Systemic Acetaminophen
FIGURE 4. Meta-analysis evaluating the effect of a single preventive dose of systemic acetaminophen on postoperative opioid consumption compared with control. The overall effect of systemic acetaminophen versus control was estimated using a random effect. Point estimate (95% confidence interval [CI]) for overall effect was 9.7 ( 13.0 to 6.4) mg morphine intravenous equivalents. Weighted mean difference for individual studies represented by square on Forrest plot with 95% CI of the difference shown as solid line. Larger sized square and thicker 95% CI line denote larger sample size. The diamond represents the pooled estimate and uncertainty for the effects of the systemic acetaminophen compared with control.
benefits of acetaminophen to prevent PONV when given as a single-dose preventive strategy. It was also interesting to note that larger doses of acetaminophen were not associated with beneficial effects on pain outcomes. A meta-regression analysis failed to detect an association between acetaminophen dose and early postoperative pain outcomes and cumulative opioid consumption. Our findings are similar to Hahn et al52 who did not detect a dose-response effect of acetaminophen on
FIGURE 5. Meta-analysis evaluating the effect of a single preventive dose of systemic acetaminophen on postoperative nausea and/or vomiting compared with control. The overall effect of systemic acetaminophen versus control was estimated using a random effect. Odds ratio (95% confidence interval [CI]) for the overall effect was 0.25 (0.13 to 0.47). Odds ratio difference for individual studies represented by square on Forrest plot with 95% CI of the difference is shown as solid line. Larger sized square and thicker 95% CI line denote larger sample size. The diamond represents the pooled estimate and uncertainty for the effects of the systemic acetaminophen compared with control. r
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postoperative pain. As patients may use oral acetaminophen postoperatively and overcome safety limits, our current results do not support the use of doses >1 g when used as a preventive intervention to reduce surgical pain. Our current quantitative analysis on systemic acetaminophen has significant methodological differences than previous ones performed by other investigators. Previous meta-analysis included studies investigating multiple dosage regimens and mixed adults and pediatric patients.12 In addition, previous authors did not discriminate between the uses of acetaminophen as a treatment versus preventive strategy.11 Those are likely reasons why previous investigators were not able to estimate an opioid-sparing effect of a single-dose acetaminophen given intravenously. In addition, they were also not able to demonstrate a reduction of PONV by systemic acetaminophen. Postoperative reduction in the consumption of opioids seems to be an important factor to improve postoperative quality of recovery in surgical patients.3,28 The reduction of opioid consumption observed in the current investigation suggests that single preventive dose of systemic acetaminophen may be a viable intervention to improve postoperative quality of recovery. Our group is currently performing a randomized clinical trial to test the hypothesis (NCT01852955) that preventive systemic acetaminophen improves postoperative quality of recovery. Our current investigation should only be interpreted in the context of its limitations. Although we limited the type of intervention (single-dose acetaminophen as a preventive strategy to minimize heterogeneity, we observed high heterogeneity in some of our analysis. However, heterogeneity was largely explained by the time of drug administration (preoperatively vs. postoperatively) and/or the quality of included studies. We also detected asymmetry of funnel plots in some of our main analysis suggesting the possibility of publication bias. It is possible that the detection of www.clinicalpain.com |
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negative unpublished trials could reduce the aggregated effect currently reported in those analyses. Finally, we did not register the current review on a database of systematic reviews. Nonetheless, our evaluated outcomes were the same as previous meta-analysis reported by our group and others on postoperative pain.6,8 In summary, systemic acetaminophen when used as a single-dose preventive regimen is an effective intervention to improve postoperative pain outcomes. In addition, systemic acetaminophen also reduces postoperative nausea and/or vomiting. Lack of dose ranging benefits on postoperative outcomes does not support the use of greater doses than 1 g as a preventive strategy. Clinical practitioners should consider the use of a single preventive dose of systemic acetaminophen to reduce pain in patients undergoing surgical procedures.
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14. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12. 15. Macintyre PE, Ready LB. Pharmacology of opioids. In: Macintyre PE, Ready LB, eds. Acute Pain Management-A Practical Guide. 2nd ed. London: W.B. Saunders; 2001:15–49. 16. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13. 17. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. 18. Egger M, Davey Smith G, Schneider M, et al. Bias in metaanalysis detected by a simple, graphical test. BM. 1997; 315:629–634. 19. De Oliveira GS Jr, Chang R, Kendall MC, et al. Publication bias in the anesthesiology literature. Anesth Analg. 2012; 114:1042–1048. 20. Rosenthal R. The file drawer problem and tolerance for null results”. Psychol Bull. 1979;86:638–641. 21. Jones VM. Acetaminophen injection: a review of clinical information. J Pain Palliat Care Pharmacother. 2011;25: 340–349. 22. de Oliveira GS Jr, Balliu B, Nader A, et al. Dose-ranging effects of intrathecal epinephrine on anesthesia/analgesia: a meta-analysis and metaregression of randomized controlled trials. Reg Anesth Pain Med. 2012;37:423–432. 23. Brett CN, Barnett SG, Pearson J. Postoperative plasma paracetamol levels following oral or intravenous paracetamol administration: a double-blind randomised controlled trial. Anaesth Intensive Care. 2012;40:166–171. 24. Yadeau JT, Paroli L, Kahn RL, et al. Addition of pregabalin to multimodal analgesic therapy following ankle surgery: a randomized double-blind, placebo-controlled trial. Reg Anesth Pain Med. 2012;37:302–307. 25. Allegaert K, Kulo A, Verbesselt R, et al. The pharmacokinetics of a high intravenous dose of paracetamol after caesarean delivery: the effect of gestational age. Eur J Anaesthesiol. 2012;29:484–488. 26. YaDeau JT, Tedore T, Goytizolo EA, et al. Lumbar plexus blockade reduces pain after hip arthroscopy: a prospective randomized controlled trial. Anesth Analg. 2012;115:968–972. 27. Avellaneda C, Go´mez A, Martos F, et al. The effect of a single intravenous dose of metamizol 2 g, ketorolac 30 mg and propacetamol 1 g on haemodynamic parameters and postoperative pain after heart surgery. Eur J Anaesthesiol. 2000; 17:85–90. 28. Lunn TH, Andersen LØ, Kristensen BB. Effect of high-dose preoperative methylprednisolone on recovery after total hip arthroplasty: a randomized, double-blind, placebo-controlled trial. Br J Anaesth. 2013;110:66–73. 29. van der Vijver RJ, van Laarhoven CJ, Lomme RM, et al. Paracetamol does not compromise early wound repair in the intestine or abdominal wall in the rat. Anesth Analg. 2012;115:1451–1456. 30. Loader J, Brooks T. Paracetamol or metronidazole? Br J Anaesth. 2013;111:301–302. 31. Zahoor A, Mateger M, Ahmad N. Is previous cholecystectomy a contraindication to paracetamol/codeine premedication? Eur J Anaesthesiol. 2013;30:131–132. 32. Mohammed BS, Engelhardt T, Cameron GA. Population pharmacokinetics of single-dose intravenous paracetamol in children. Br J Anaesth. 2012;108:823–829. 33. Cok OY, Eker HE, Pelit A, et al. The effect of paracetamol on postoperative nausea and vomiting during the first 24 h after strabismus surgery: a prospective, randomised, doubleblind study. Eur J Anaesthesiol. 2011;28:836–841. 34. Dejonckheere M, Desjeux L, Deneu S, et al. Intravenous tramadol compared to propacetamol for postoperative analgesia following thyroidectomy. Acta Anaesthesiol Belg. 2001;52:29–33. 35. Fenlon S, Collyer J, Giles J, et al. Oral vs. intravenous paracetamol for lower third molar extractions under general r
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anaesthesia: is oral administration inferior? Br J Anaesth. 2013;110:432–437. Tunali Y, Akc¸il EF, Dilmen OK, et al. Efficacy of intravenous paracetamol and dexketoprofen on postoperative pain and morphine consumption after a lumbar disk surgery. J Neurosurg Anesthesiol. 2013;25:143–147. Brodner G, Gogarten W, Van Aken H, et al. Efficacy of intravenous paracetamol compared to dipyrone and parecoxib for postoperative pain management after minor-to-intermediate surgery: a randomised, double-blind trial. Eur J Anaesthesiol. 2011;28:125–132. Ohnesorge H, Bein B, Hanss R, et al. Paracetamol versus metamizol in the treatment of postoperative pain after breast surgery: a randomized, controlled trial. Eur J Anaesthesiol. 2009;26:648–653. Alhashemi JA, Alotaibi QA, Mashaat MS, et al. Intravenous acetaminophen vs oral ibuprofen in combination with morphine PCIA after cesarean delivery. Can J Anaesth. 2006; 53:1200–1206. Hiller A, Helenius I, Nurmi E. Acetaminophen improves analgesia but does not reduce opioid requirement after major spine surgery in children and adolescents. Spine (Phila Pa 1976). 2012;37:E1225–E1231. Hynes D, McCarroll M, Hiesse-Provost O. Analgesic efficacy of parenteral paracetamol (propacetamol) and diclofenac in post-operative orthopaedic pain. Acta Anaesthesiol Scand. 2006;50:374–381. Khalili G, Janghorbani M, Saryazdi H, et al. Effect of preemptive and preventive acetaminophen on postoperative pain score: a randomized, double-blind trial of patients undergoing lower extremity surgery. J Clin Anesth. 2013; 25:188–192. Olonisakin RP, Amanor-Boadu SD, Akinyemi AO. Morphinesparing effect of intravenous paracetamol for post operative pain management following gynaecological surgery. Afr J Med Med Sci. 2012;41:429–436. Arslan M, Cic¸ek R, Celep B, et al. Comparison of the analgesic effects of intravenous paracetamol and lornoxicam in postoperative pain following thyroidectomies. Agri. 2011;23: 160–166. Moon YE, Lee YK, Lee J, et al. The effects of preoperative intravenous acetaminophen in patients undergoing abdominal hysterectomy. Arch Gynecol Obstet. 2011;284: 1455–1460. Sen H, Kulahci Y, Bicerer E, et al. The analgesic effect of paracetamol when added to lidocaine for intravenous regional anesthesia. Anesth Analg. 2009;109:1327–1330. Salihoglu Z, Yildirim M, Demiroluk S, et al. Evaluation of intravenous paracetamol administration on postoperative pain
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and recovery characteristics in patients undergoing laparoscopic cholecystectomy. Surg Laparosc Endosc Percutan Tech. 2009;19:321–323. Salonen A, Silvola J, Kokki H. Does 1 or 2 g paracetamol added to ketoprofen enhance analgesia in adult tonsillectomy patients? Acta Anaesthesiol Scand. 2009;53:1200–1206. Arici S, Gurbet A, Tu¨rker G, et al. Preemptive analgesic effects of intravenous paracetamol in total abdominal hysterectomy. Agri. 2009;21:54–61. Api O, Unal O, Ugurel V, et al. Analgesic efficacy of intravenous paracetamol for outpatient fractional curettage: a randomised, controlled trial. Int J Clin Pract. 2009;63: 105–111. Silvanto M, Munsterhjelm E, Savolainen S, et al. Effect of 3 g of intravenous paracetamol on post-operative analgesia, platelet function and liver enzymes in patients undergoing tonsillectomy under local anaesthesia. Acta Anaesthesiol Scand. 2007;51:1147–1154. Hahn TW, Mogensen T, Lund C, et al. Analgesic effect of i.v. paracetamol: possible ceiling effect of paracetamol in postoperative pain. Acta Anaesthesiol Scand. 2003;47:138–145. Joshi GP, Ahmad S, Riad W, et al. Selection of obese patients undergoing ambulatory surgery: a systematic review of the literature. Anesth Analg. 2013;5:1082–1091. Bergmann I, Go¨hner A, Crozier TA, et al. Surgical pleth indexguided remifentanil administration reduces remifentanil and propofol consumption and shortens recovery times in outpatient anaesthesia. Br J Anaesth. 2013;110:622–628. De Oliveira GS Jr, Castro-Alves LJ, Ahmad S, et al. Dexamethasone to prevent postoperative nausea and vomiting: an updated meta-analysis of randomized controlled trials. Anesth Analg. 2013;116:58–74. De Oliveira GS Jr, Castro-Alves LJ, Chang R, et al. Systemic metoclopramide to prevent postoperative nausea and vomiting: a meta-analysis without Fujii’s studies. Br J Anaesth. 2012;109:688–697. Harsten A, Kehlet H, Toksvig-Larsen S. Recovery after total intravenous general anaesthesia or spinal anaesthesia for total knee arthroplasty: a randomized trial. Br J Anaesth. 2013;111:391–399. Fawcett WJ, Mythen MG, Scott MJ. Enhanced recovery: more than just reducing length of stay? Br J Anaesth. 2012;109: 671–674. Tzimas P, Prout J, Papadopoulos G, et al. Epidural anaesthesia and analgesia for liver resection. Anaesthesia. 2013; 68:628–635. Apfel CC, Turan A, Souza K, et al. Intravenous acetaminophen reduces postoperative nausea and vomiting: a systematic review and meta-analysis. Pain. 2013;154:677–689.
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Single-dose Systemic Acetaminophen to Prevent Postoperative Pain A Meta-analysis of Randomized Controlled Trials Gildasio S. De Oliveira, Jr, MD, MSCI, Lucas J. Castro-Alves, MD, and Robert J. McCarthy, PharmD
Objectives: The effect of a single-dose systemic acetaminophen to treat postoperative pain has been previously quantified, but the effect of systemic acetaminophen to prevent postoperative pain is currently not well defined. The preventive analgesic effect of acetaminophen has yet to be quantified in a meta-analysis. The objective of the current investigation was to evaluate the effect of a single preventive dose of systemic acetaminophen on postoperative pain outcomes. Materials and Methods: A wide search was performed to identify randomized controlled trials that evaluated the effects of a single dose of systemic acetaminophen on pain outcomes in a large variety of surgical procedures. Meta-analysis was performed using a random-effect model. Results: Eleven randomized clinical trials evaluating 740 patients were included in the analysis. The weighted mean difference (95% confidence interval [CI]) of the combined effects favored acetaminophen over control for early pain at rest (r4 h, 1.1 ( 2.0 to 0.2)) and early pain at movement (24 h, 1.9 ( 2.8 to 1.0)) Postoperative opioid consumption was decreased in the systemic acetaminophen group compared with control. Weighted mean difference (95% CI) of 9.7 ( 13.0 to 6.4) mg morphine intravenous equivalents systemic acetaminophen also reduced postoperative nausea and vomiting compared with control, odds ratio (95% CI) of 0.25 (0.13 to 0.47), numbers needed to treat (95% CI) = 3.3 (2.3 to 5.9).
modalities can result in better postoperative pain control for surgical patients.4,5 However, phramacological interventions that are effective to treat postoperative pain may not have the same efficacy when examined as a preventive analgesic strategy.6,7 In addition, the fast hospital discharge of ambulatory patients or undesirable side effects may only allow a single-dose administration of a systemic analgesic drug.8–10 Systemic acetaminophen has been used in Europe for many years but only recently it became available in the United States. Several clinical studies have examined the use of systemic acetaminophen in the perioperative setting with varying results. In addition, previous quantitative systematic reviews did not differentiate between a preventive versus a treatment effect of the drug.11,12 It is, therefore, unknown if systemic acetaminophen, when given as single dose, is an effective strategy to prevent postsurgical pain. The main objective of the current investigation was to examine the effect of systemic acetaminophen on postoperative pain outcomes when the drug was given as a preventive analgesic strategy. We also sought to investigate a possible association between acetaminophen dosage and drug effects on postoperative pain outcomes.
Discussion: Systemic acetaminophen, when used as a single-dose preventive regimen, is an effective intervention to reduce postoperative pain. It also reduces postoperative nausea and/or vomiting. Doses >1 g were not associated with greater reduction in pain outcomes.
We performed a quantitative systematic review following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.13
Key Words: acetaminophen, pain, preventive, surgery
Systematic Search
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I
mprovement of postoperative pain outcomes seems to be an important pathway to ameliorate patients’ quality of postsurgical recovery.1–3 The use of preventive analgesic
Received for publication November 1, 2013; revised February 25, 2014; accepted January 27, 2014. From the Department of Anesthesiology, Northwestern University, Chicago, IL. Supported by Department of Anesthesiology, Northwestern University, Chicago, IL. Dr De Oliveira has received a research Grant from Cadence Pharmaceuticals. Cadence pharmaceuticals was not involved in any aspect in the study. The other authors declare no conflict of interest. Reprints: Gildasio S. De Oliveira Jr, MD, MSCI, Department of Anesthesiology, Northwestern University, 241 East Huron St F5704, 60611 Chicago, IL (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins DOI: 10.1097/AJP.0000000000000081
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MATERIALS AND METHODS
Published reports of randomized trials evaluating the effects of intravenous acetaminophen on surgical postoperative pain were searched using the National Library of Medicine’s PubMed database, the Cochrane Database of Systematic Reviews and Google Scholar inclusive to July 1, 2013. Free text and MeSH terms “acetaminophen,” “propacetamol,” “paracetamol,” “pain,” “preoperative,” “analgesia,” “surgery,” and “opioid” were used individually and in pairwise combinations. No language restriction was used. An attempt to identify additional studies not found by the primary search methods was made by reviewing the reference lists from identified studies. No search was performed for unpublished studies. This initial search yielded 491 manuscripts.
Selection of Included Studies The study’s inclusion and exclusion criteria were determined before the systematic search. Two authors (G.S.D.O. and L.J.C.A.) independently evaluated the abstract and results of the 491 articles obtained by the Clin J Pain
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initial search. Articles that were clearly not relevant based on our inclusion and exclusion criteria were excluded at this phase. Disagreements on inclusion of the articles were resolved by discussion among the evaluators. If an agreement could not be reached, the dispute was resolved with the help of a third investigator (R.J.M,). The third investigator was blinded regarding evaluation of the first 2 authors.
Inclusion and Exclusion Criteria We included randomized controlled trials that compared a single-dose intravenous acetaminophen preoperative or intraoperative with an inactive (placebo or “no treatment”) control group in patients undergoing surgical procedures. Studies containing a concurrent use of an alternative multimodal analgesia regimen were excluded if a direct comparison of acetaminophen and control could not be established. Comparisons that examined acetaminophen for treatment of postoperative pain but not for prevention (preoperative or intraoperative administration) were also excluded. Included studies had to report at least on pain scores or opioid consumption as postoperative pain outcomes. No minimum sample size was required for inclusion in the meta-analysis.
Validity Scoring Two authors (G.S.D.O. and L.J.C.A.) independently read the included reports and assessed their methodological validity using a modified Jadad 5-point quality scale.14 The scale evaluates the study for the following: randomization, double-blind evaluation, concealment of study group to evaluator, valid randomization method, and completeness of data at follow-up.
Data Extraction Two authors (G.S.D.O. and L.J.C.A.) independently evaluated the full manuscripts of all included trials and performed data extraction using a data collection form specifically developed for this review. Data extracted from trials included the acetaminophen dose, time of drug administration (preoperatively or intraoperatively at the end of surgery), sample size, number of patients in treatment groups, follow-up period, type of surgery, early pain scores (r4 h) at rest and at movement, late pain scores (24 h) at rest and at movement, cumulative opioid consumption, time to rescue analgesic administration (min), and adverse events. Postoperative opioid consumption was converted to the equivalent dose of intravenous morphine.15 Visual analog scale of pain were converted to a 010 numeric rating scale. Data presented only as median and range was converted to means and SD using previously described methodology.16
Single-dose Systemic Acetaminophen
Meta-Analysis The weighted mean differences (WMDs) with 95% confidence interval (CI) were determined and reported for continuous data. For dichotomous data (adverse effects), the Peto odds ratio (OR) (to account for the potential of zero counts in the cells for low-frequency outcomes) and 95% CI are reported. For primary outcomes, a significant effect compared with placebo required that the 95% CI for continuous data did not include zero and for dichotomous secondary data, the 95% confidence interval did not include 1.0. Because of the different surgical procedures, we used a random-effect model in an attempt to generalize our findings to studies not included in our meta-analysis.17 Publication bias was evaluated by examining for asymmetric funnel plots using Egger and colleague’s regression test.18,19 A file drawer analysis described by Rosenthal20 was performed in the case of an asymmetric funnel plot. The conversion of propacetamol to paracetamol was performed using a 2:1 ratio as previously recommended.21 Heterogeneity of the included studies was further evaluated if the I2 statistic was >50%. Further analysis was planned a priori to explore nontrivial heterogeneity of the treatment effect across the included studies including time of drug administration (preoperatively vs. intraoperatively at the end of surgery) and quality of included studies evaluated by the Jadad score. The proportion of the total variance explained by the covariates (R2) was calculated by dividing the random-effects pooled estimates of variance (t2) within studies by the total variance (total t2). The value obtained was then subtracted from 1. When values fall outside the range of 0% to 100%, they were set to the closest value (0% or 100%). A meta-regression analysis was performed to evaluate a possible association between total acetaminophen dose and the effect size on evaluated outcomes.22 In studies that reported a weight-based dosage, the total value was obtained using the mean reported weight. In cases that weight was not reported, 70 kg was used a reference value. Analysis was performed using Stata version 13 (College Station, TX) and Comprehensive Meta-analysis software version 2 (Biostat, Englewood, NJ).
RESULTS
Early acute postoperative pain scores (visual analog scale) at rest and at movement (0 to 4 h postoperatively; late acute postoperative pain scores (visual analog scale) at rest and at movement (24 h postoperatively); and cumulative opioid consumption (24 h) in the postoperative period.
Of the initially evaluated abstracts, 30 studies initially met the inclusion criteria (Fig. 1). Nineteen studies were subsequently excluded: 6 studies did not report on evaluated outcomes or comparisons,23–28 1 study was not performed in humans,29 2 manuscripts were not randomized trials,30,31 2 evaluated children,32,33 3 did not provide a direct comparison between systemic acetaminophen and control,34–36 and 5 evaluated multiple doses.37–41 The characteristics of the 11 included studies are listed in Table 1. The evaluated trials included data from 740 patients and were published between 2003 and 2013.42–52 The median and interquartile range number of patients of the included studies receiving IV acetaminophen was 36 (28 to 50). The median and interquartile range of the modified Jadad scale score was 4 (3 to 5). All 11 studies reported on opioid consumption and/or pain scores. Three studies reported pain scores for both rest and activity.45,49,52
Secondary Outcomes
Early (0 to 4 h) Pain at Rest
The time to first analgesic administration (min); adverse events including: pruritus, postoperative nausea, and/or vomiting.
The aggregate effect of the 9 studies (13 comparisons) evaluating the effect of systemic acetaminophen on early pain at rest favored acetaminophen over control with a
Definition of Relevant Outcome Data Primary Outcomes
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compared with control did not reveal a benefit in relation to a large confidence interval, WMD (95% CI) of 0.4 ( 0.9 to 0.05) (0-10 numerical scale). Heterogeneity was high (I2 = 72%). The variance was not altered by time of drug administration (preoperatively vs. postoperatively). In contrast, 100% of the heterogeneity could be explained by lower quality studies (Jadadr3) with low heterogenity among higher quality studies (I2 = 0).
Late Pain (24 h) at Movement Only 2 studies examined the effect of systemic acetaminophen on late pain at movement compared with control. The study of Moon et al45 did not reveal a significant effect in relation to a large confidence interval, WMD (95% CI) of 0.2( 1.1 to 0.7) (0-10 numerical scale). In contrast, the study of Arici et al49 showed a significant effect of acetaminophen on late pain at movement when compared with control, WMD (95% CI) of 2.7 ( 3.6 to 1.7).
Postoperative Opioid Consumption (up to 24 h)
FIGURE 1. Flowchart outlining retrieved, excluded, and evaluated randomized controlled trials.
WMD (95% CI) of 1.1 ( 2.0 to 0.2).45–52 (0-10 numerical scale) (Fig. 2). Three studies provided >1 independent comparisons that were included in the analysis.48,49,52 There was no evidence of publication bias as given by the test for an asymmetric funnel plot (P = 0.21). Heterogeneity was high (I2 = 87) but it could be explained by the by time of drug administration (preoperatively vs. postoperatively) with a low heterogeneity when the drug was administered preoperatively (I2 = 19). A meta-regression analysis did not identify an association between the acetaminophen dose administered and an effect on early pain at rest (Slope (95% CI) = 0.4 ( 0.89 to 1.70), P = 0.53 compared with slope = 0).
The aggregated effect of 9 studies (14 comparisons)42–45,47–49,51,52 evaluating the effect of systemic acetaminophen on postoperative opioid consumption compared with control favored acetaminophen, WMD (95% CI) of 9.7 ( 13.0 to 6.4) mg morphine intravenous equivalents (Fig. 4). Four studies provided >1 independent comparisons that were included in the analysis.42,48,49,52 The funnel plot demonstrated asymmetry (P = 0.02) suggesting the possibility of publication bias. It would be required to detect 14 missing negative studies to significantly change the analysis. Heterogeneity was high (I2 = 97%) and it could not be explained by time of the drug administration (preoperatively vs. postoperatively). In contrast, 36% of the total variance could be explained by the inclusion of lower quality studies (Jadadr3). The opioid-sparing effect was greater when preventive acetaminophen was given for patients undergoing procedures with general anesthesia, WMD (95% CI) of 13.2( 18.5 to 7.8) mg of IV morphine equivalents compared with 3.1 ( 5.2 to 0.9) mg of IV morphine equivalents when acetaminophen was given to patients undergoing regional/local anesthesia, P = 0.006. A metaregression analysis did not suggest an association between the acetaminophen dose administered and the effect on postoperative opioid consumption (Slope (95% CI) = 4.6 ( 1.3 to 10.7), P = 0.12 compared with slope = 0).
Time to First Analgesic Administration (min) Early (0 to 4 h) Pain at Movement The overall effect of 3 studies (6 comparisons)45,49,52 evaluating the effect of systemic acetaminophen on early pain at movement compared with control favored acetaminophen, WMD (95% CI) of 1.9 ( 2.8 to 1.0) (0-10 numerical scale) (Fig. 3) Two studies provided >1 independent comparisons that were included in the analysis.49,52 Egger and colleague’s regression suggested the possibility of publication bias (P = 0.047). Rosenthal and colleagues’ analysis revealed that 6 additional negative studies would be required to change the results. Heterogeneity was high (I2 = 70) and it could be explained 100% by the preoperative administration of the drug.
Late (24 h) Pain at Rest The overall effect of 5 studies (7 comparisons)42,44–46,49 examining systemic acetaminophen on late pain at rest
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Six studies (8 comparisons) evaluating the effect of systemic acetaminophen on time to first analgesic administration demonstrated a significant effect compared with control, WMD (95% CI) of 14.9 (7.2 to 22.6) minutes.42–44,47–49 Two studies reported >1 independent comparisons that were included in the analysis.42,48 The funnel plot was not asymmetric (P = 0.07). Heterogeneity was high (I2 = 95%) and it could not be explained by the time of drug administration or the quality of included studies.
Safety Analysis Postoperative Nausea and/or Vomiting The aggregated effect of 3 studies (4 comparisons) of systemic acetaminophen on postoperative nausea and/or vomiting favored acetaminophen compared with placebo, OR (95% CI) of 0.25 (0.13 to 0.47),44,45,49 numbers needed r
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TABLE 1. Summary of Studies Included in Analysis
References Khalili et al42
Procedures Lower extremity orthopedic
Olonisakin Gynecologic surgery et al43
Number Treatment/ Control 50/25
28/28
Arslan et al44
Thyroidectomy
30/30
Moon et al45
Hysterectomy
36/35
Sen et al46
Hand surgery
20/20
Salihoglu et al47
Laparoscopic cholecystectomy
20/20
Salonen et al48
Tonsillectomy
76/38
Arici et al49 Abdominal hysterectomy
55/27
Api et al50
Curretage
36/34
Silvanto et al51
Tonsillectomy
35/36
Hahn et al52
Laparoscopic tubal ligation
45/16
Treatment
Type of Anesthesia
Acetaminophen Spinal 0.5% 15 mg/kg before bupivacaine beginning of surgery or Acetaminophen 15 mg/kg at the end of surgery Acetaminophen 1 g Not at the end of standardized surgery Acetaminophen 1 g Thiopental/ at the end of fentanyl/ surgery isofurane/ nitrous oxide Acetaminophen 2 g Propofol/ before beginning fentanyl/ of surgery sevofurane/ nitrous oxide Acetaminophen IV regional 300 mg before block with beginning of lidocaine surgery Acetaminophen 1 g Propofol/ before beginning remifentaof surgery nil/ desflurane Acetaminophen 1 g Propofol/ or 2 g at the end fentanyl/ of surgery sevoflurane/ nitrous oxide Acetaminophen 1 g Propofol/ before beginning fentanyl/ or sevoflurane/ Acetaminophen 1 g nitrous at the end of oxide surgery Acetaminophen 1 g Not before beginning standardized of surgery Acetaminophen 3 g Local before beginning infiltration of surgery with lidocaine Acetaminophen Propofol/ 1.4 g or 0.66 g or remifentanil 0.34 g at the end of surgery
Postoperative Analgesia
Modified Jadad Method of Data Score (1-5)14 Extraction ASA Class
Meperidine 0.05 mg/kg IV
5
Text/table
I, II
Morphine 2 mg IV
3
Table/text
I, II
Tramadol IV
3
Table/text
I, II
Hydromorphone 0.2 mg PCA IV
5
Table/text/ I, II figure
Fentanyl 1 mcg/ kg IV
4
Table/text
I, II
Morphine 2 mg IV
4
Table/text
I, II
Oxycodone 2 mg IV
5
Table/text/ I, II figure
Morphine IV PCA
2
Table/text/ I, II figure
Not standardized
4
Text
Morphine IV PCA
4
Table/text/ I, II figure
Alfentanil 0.1 mg IV PCA
4
Table/text/ I, II figure
Not described
PCA indicates patient controlled analgesia.
to treat (95% CI) = 3.3 (2.3 to 5.9) (Fig. 5). One study provided >1 independent comparisons that were included in the analysis.49 There was no evidence for an asymmetric funnel plot (P = 0.48). Heterogeneity was low (I2 = 0).
0.47 (0.04 to 5.4). In contrast, the study of Araci et al49 demonstrated a reduction on the incidence of pruritus by acetaminophen, OR (95% CI) of 0.1 (0.07 to 0.65).
Major Side Effects
Pruritus
None of the included studies reported any cases of major side effects (liver damage, anaphylaxis, renal failure).
Two studies evaluated the effect of systemic acetaminophen on the incidence of postoperative pruritus. The study of Moon et al45 did not show a significant benefit of acetaminophen compared with control, OR (95% CI) of
The most important finding of the current investigation was the clinically significant effect of systemic
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FIGURE 2. Meta-analysis evaluating the effect of a single preventive dose of systemic acetaminophen on early pain scores (r4 h) at rest compared with control. The overall effect of systemic acetaminophen versus control was estimated using a random effect. Point estimate (95% confidence interval [CI]) for overall effect was 1.1 ( 2.0 to 0.2) (0-10 numerical scale). Weighted mean difference for individual studies represented by square on Forrest plot with 95% CI of the difference shown as solid line. Larger sized square and thicker 95% CI line denote larger sample size. The diamond represents the pooled estimate and uncertainty for the effects of the systemic acetaminophen compared with control.
acetaminophen on analgesia outcomes when given as a single-dose preventive strategy. A single-dose acetaminophen promoted a large reduction in postoperative opioid consumption (approximately 10 mg IV morphine equivalents). In addition, early pain outcomes (rest and movement) were also improved postoperatively in patients who received systemic acetaminophen. Taken together, our results suggest that a single preventive dose of systemic acetaminophen is an effective intervention to mitigate postsurgical pain. Surgical procedures performed in an outpatient setting continue to grow around the world.53,54 The fast discharge of ambulatory patients or the fear for potential side effects may only allow a single dose of systemic acetaminophen to be administered. Our current results support the preventive
use of acetaminophen as an effective intervention in those circumstances. Another important finding of the current investigation was the reduction of postoperative nausea and/or vomiting in patients who received a single-dose systemic acetaminophen compared with control. The effect was comparable with other commonly used antiemetics.55,56 It is not unusual for established perioperative pain interventions to be unable to demonstrate benefits on opioid-related side effects and other recovery measures.57–59 Apfel et al60 has recently demonstrated the benefit of acetaminophen to prevent postoperative nausea and vomiting (PONV) but the authors did not discriminate in regards to number of dosages and treatment versus preventive strategy. Our current results extend the findings of Apfel and colleagues on the
FIGURE 3. Meta-analysis evaluating the effect of a single preventive dose of systemic acetaminophen on early pain scores (r4 h) at movement compared with control. The overall effect of systemic acetaminophen versus control was estimated using a random effect. Point estimate (95% confidence interval [CI]) for overall effect was 1.9 ( 2.8 to 1.0) (0-10 numerical scale). Weighted mean difference for individual studies represented by square on Forrest plot with 95% CI of the difference shown as solid line. Larger sized square and thicker 95% CI line denote larger sample size. The diamond represents the pooled estimate and uncertainty for the effects of the systemic acetaminophen compared with control.
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FIGURE 4. Meta-analysis evaluating the effect of a single preventive dose of systemic acetaminophen on postoperative opioid consumption compared with control. The overall effect of systemic acetaminophen versus control was estimated using a random effect. Point estimate (95% confidence interval [CI]) for overall effect was 9.7 ( 13.0 to 6.4) mg morphine intravenous equivalents. Weighted mean difference for individual studies represented by square on Forrest plot with 95% CI of the difference shown as solid line. Larger sized square and thicker 95% CI line denote larger sample size. The diamond represents the pooled estimate and uncertainty for the effects of the systemic acetaminophen compared with control.
benefits of acetaminophen to prevent PONV when given as a single-dose preventive strategy. It was also interesting to note that larger doses of acetaminophen were not associated with beneficial effects on pain outcomes. A meta-regression analysis failed to detect an association between acetaminophen dose and early postoperative pain outcomes and cumulative opioid consumption. Our findings are similar to Hahn et al52 who did not detect a dose-response effect of acetaminophen on
FIGURE 5. Meta-analysis evaluating the effect of a single preventive dose of systemic acetaminophen on postoperative nausea and/or vomiting compared with control. The overall effect of systemic acetaminophen versus control was estimated using a random effect. Odds ratio (95% confidence interval [CI]) for the overall effect was 0.25 (0.13 to 0.47). Odds ratio difference for individual studies represented by square on Forrest plot with 95% CI of the difference is shown as solid line. Larger sized square and thicker 95% CI line denote larger sample size. The diamond represents the pooled estimate and uncertainty for the effects of the systemic acetaminophen compared with control. r
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postoperative pain. As patients may use oral acetaminophen postoperatively and overcome safety limits, our current results do not support the use of doses >1 g when used as a preventive intervention to reduce surgical pain. Our current quantitative analysis on systemic acetaminophen has significant methodological differences than previous ones performed by other investigators. Previous meta-analysis included studies investigating multiple dosage regimens and mixed adults and pediatric patients.12 In addition, previous authors did not discriminate between the uses of acetaminophen as a treatment versus preventive strategy.11 Those are likely reasons why previous investigators were not able to estimate an opioid-sparing effect of a single-dose acetaminophen given intravenously. In addition, they were also not able to demonstrate a reduction of PONV by systemic acetaminophen. Postoperative reduction in the consumption of opioids seems to be an important factor to improve postoperative quality of recovery in surgical patients.3,28 The reduction of opioid consumption observed in the current investigation suggests that single preventive dose of systemic acetaminophen may be a viable intervention to improve postoperative quality of recovery. Our group is currently performing a randomized clinical trial to test the hypothesis (NCT01852955) that preventive systemic acetaminophen improves postoperative quality of recovery. Our current investigation should only be interpreted in the context of its limitations. Although we limited the type of intervention (single-dose acetaminophen as a preventive strategy to minimize heterogeneity, we observed high heterogeneity in some of our analysis. However, heterogeneity was largely explained by the time of drug administration (preoperatively vs. postoperatively) and/or the quality of included studies. We also detected asymmetry of funnel plots in some of our main analysis suggesting the possibility of publication bias. It is possible that the detection of www.clinicalpain.com |
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negative unpublished trials could reduce the aggregated effect currently reported in those analyses. Finally, we did not register the current review on a database of systematic reviews. Nonetheless, our evaluated outcomes were the same as previous meta-analysis reported by our group and others on postoperative pain.6,8 In summary, systemic acetaminophen when used as a single-dose preventive regimen is an effective intervention to improve postoperative pain outcomes. In addition, systemic acetaminophen also reduces postoperative nausea and/or vomiting. Lack of dose ranging benefits on postoperative outcomes does not support the use of greater doses than 1 g as a preventive strategy. Clinical practitioners should consider the use of a single preventive dose of systemic acetaminophen to reduce pain in patients undergoing surgical procedures.
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