Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia

J. Rømsing*,1, S. Møiniche2 and J. B. Dahl2

1Department of Pharmaceutics, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark. 2Department of Anaesthesiology, Herlev University Hospital, Herlev, Denmark.*Corresponding author

Accepted for publication: June 12, 2001


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. We have reviewed the analgesic efficacies of rectal and parenteral paracetamol and tested the evidence for a possible additive analgesic effect of the combination of paracetamol with a non-steroidal anti-inflammatory drug (NSAID) in postoperative pain.

Methods. Randomized controlled trials were evaluated. Outcome measures were pain scores and demand for supplementary analgesia.

Results. Eight studies compared rectal paracetamol with placebo. One study of single-dose administration of rectal paracetamol 40–60 mg kg–1 and three studies of repeat dosing with 14–20 mg kg–1 showed significant analgesic efficacy, while studies of a single dose of 10–20 mg kg–1 were negative. Ten studies compared parenteral paracetamol with placebo and eight studies showed improved pain relief with paracetamol. Of the nine studies comparing paracetamol with a combination of paracetamol and an NSAID, six studies showed improved pain relief for the combination while only two of the six studies comparing an NSAID with a combination of an NSAID and paracetamol showed improved pain relief for the combination.

Conclusions. Considering the few studies available, evidence was found of a clinically relevant analgesic effect of rectal and parenteral paracetamol. Concurrent use of paracetamol and an NSAID was superior to paracetamol alone but no evidence was found of superior analgesic effect of the combination compared with the NSAID alone.

Br J Anaesth 2002; 88: 215–26

Keywords: analgesics non-opioid, paracetamol; analgesics anti-inflammatory, non-steroidal; pain, postoperative; anaesthesia, audit


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Paracetamol is frequently used as a non-opioid analgesic in postoperative pain. Its mechanism of action is not fully understood, but it is generally accepted that paracetamol is a centrally acting drug.1 2 The analgesic effect of paracetamol is probably dependent on the rate and amount of active drug reaching the CNS, where its analgesic effect takes place.3 Paracetamol is available as oral, rectal and injectable formulations. Reports of analgesic efficacy and adverse effects of oral paracetamol have been the subject of recent systematic reviews,48 but evidence-based estimates of clinical analgesic effects of rectal and parenteral paracetamol in postoperative pain are not available.

When pain relief is insufficient with paracetamol alone, a non-steroidal anti-inflammatory drug (NSAID) may be added in combination. NSAIDs inhibit prostaglandin synthesis in peripheral tissues. Some suggest a peripheral– central synergistic action of NSAIDs that varies depending on the particular NSAID and on the presence of an inflammatory process.9 Concomitant administration of two analgesics with presumably different mechanisms of action may be more effective than the use of either drug alone and may reduce the need for supplementary analgesics after surgery. The combination of paracetamol and NSAIDs is widely used clinically, but consensus on whether such a combination offers a clinically relevant improvement in analgesia is still lacking.

The aim of this systematic review was, first, to review the analgesic efficacy of rectally or parenterally administered paracetamol for postoperative pain relief, and secondly to test the evidence for a possible additive analgesic effect of the combination of paracetamol and an NSAID compared with either drug alone in postoperative pain.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Randomized controlled trials (RCTs) of rectal or parenteral paracetamol, of comparisons of paracetamol given by different routes and of paracetamol in combination with an NSAID (given by any route) for postoperative analgesia were identified using Medline (1966–2000), Embase (1989–2000) and the Cochrane Library (2000) without language restriction, using the words ‘paracetamol’, ‘acetaminophen’, ‘propacetamol’, ‘NSAID’, ‘non-steroidal anti-inflammatory drug’, individual drug names and ‘postoperative pain’. We last carried out a search in December 2000. Additional reports were identified from reference lists of retrieved reports. Abstracts or unpublished observations were not considered.

Criteria for inclusion
For the first part of the review, reports were considered if they were (i) comparisons of rectal paracetamol with placebo/no treatment, (ii) comparisons of i.v./i.m. paracetamol (propacetamol) with placebo/no treatment, (iii) comparisons of different doses of rectal or i.v./i.m. paracetamol, or (iv) direct comparisons of the same dose of paracetamol given by different routes. Only trials with postoperative pain as an outcome were considered. For the second part of the review, reports were considered if they were (v) comparisons of a combination of paracetamol and an NSAID with the same dose and route of administration of either drug alone for postoperative analgesia, in order to test the evidence for an additive effect of the combination.

Each report which met the inclusion criteria was read independently by all of the authors to assess adequacy of randomization and blinding and to assess the description of withdrawls.10 Consensus was achieved subsequently. Reports which were described as randomized were given one point, and a further point if the method of randomization was described and considered adequate (table of random numbers, computer-generated, etc.). If the method of randomization was inappropriate (patients were allocated alternately or according to date of birth, hospital number, etc.) one point was deducted. Reports that were described as double-blind were given one point. If the method of blinding was described and considered appropriate (identical appearance of preparation, double-dummy design, etc.) one additional point was given. If the method of blinding was inappropriate (e.g. comparison of tablet versus injection with no double dummy) one point was deducted. Reports that described the numbers of and reasons for withdrawals were given one point. As there was a prior agreement that reports without randomization would be excluded, the minimum score of an included RCT was 1 and the maximum score was 5. The validity criterion for the inclusion of studies was >=10 patients per treatment group.11 Furthermore, scores for intensity of pain were noted. It has been recognized that adequate sensitivity in trials of analgesics for acute pain is only achieved in patients experiencing at least moderate pain [visual analogue scale (VAS) >30 mm] before administration of treatment, since it is difficult to detect an improvement with a low degree of pain or no pain.12 13

Data collected
Information about drugs, doses and routes of administration, numbers of patients enrolled and analysed, types of surgery, study design, observation periods, outcome measures and adverse effects was collected on standard collection sheets.

L’Abbé plots of visual analogue scale (VAS) pain scores and of consumption of supplementary morphine were constructed to analyse the degree of pain relief and homogeneity of the data in studies comparing paracetamol with placebo/no treatment and in studies comparing a combination of paracetamol and an NSAID with either drug alone.11 If the scatter of the individual trials lay predominantly between the line of equality and the control axis, this was taken to indicate efficacy with paracetamol or with the combination of paracetamol and an NSAID and relative homogeneity.

A quantitative analysis was proposed, with calculation of the weighted mean difference (WMD) of VAS scores between treatment groups, taking into account study size and the standard deviations of the VAS scores in the individual trials (using Review Manager software version 3.11; Cochrane Collaboration, Nordic Cochrane Center, Copenhagen, Denmark). Studies using pain scores other than VAS (e.g. verbal rating scale (VRS)) were also included in the quantitative analysis if data could be converted. However, we recognized the possibility that the data would not allow quantitative analysis. Therefore, analgesic efficacy was also evaluated qualitatively by significant difference (P<0.05, as reported in the original investigation) between treatment and control arms in pain intensity using pain scores, consumption of supplementary analgesics and/or time to first analgesic request as outcome measures, and by evaluation of the clinical significance of the differences observed.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
A total of 28 trials were identified,1441 of which four were subsequently excluded because of duplicate publication23 and lack of information about randomization.24 35 36 Data from 24 RCTs, including 37 comparisons involving 2023 patients, of whom 1239 received paracetamol, were analysed. Eight studies compared rectal paracetamol with placebo or different doses of paracetamol,1421 10 compared parenteral paracetamol with placebo,22 2533 two compared the same dose of paracetamol given by different routes,30 34 nine compared paracetamol with a combination of paracetamol and an NSAID,18 21 31 33 3741 and six compared an NSAID with a combination of an NSAID and paracetamol.18 31 33 38 40 41 The range of numbers of patients included in the studies was 11–217. The median quality score of the studies was 3 (range 1–5). Details of the studies included are shown in Tables 15.


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Table 1 Comparisons of rectal paracetamol with placebo and different doses of paracetamol. P<0.05=significant difference between rectal paracetamol group and placebo group or between groups of different doses of paracetamol; n.s.=not significant; –=not evaluated; *calculated from demographic data
 

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Table 5 Comparisons of an NSAID with a combination of an NSAID and paracetamol. PCM=paracetamol; P<0.05=significant difference between NSAID group and NSAID and PCM group; n.s.=not significant;–=not evaluated
 
Quantitative analysis of VAS pain scores was performed only with reports of i.v. propacetamol. For the other reports (rectal paracetamol and combinations of paracetamol and NSAID), lack of data allowed only qualitative analysis. Instead, any statistical difference between treatments in these reports was extracted from the original investigations and documented in table format, as has been done in other systematic qualitative reviews.4244

Rectal paracetamol versus placebo and different doses of paracetamol
Seven studies with nine treatment arms compared rectal paracetamol with placebo1420 and one study with two treatment arms compared two doses of rectal paracetamol21 (Table 1). In five trials rectal paracetamol was administered before surgery14 15 17 18 21 and in three trials paracetamol was administered after surgery.16 19 20 In one study, paracetamol was administered as a rectal solution.14 Only in three studies was information about the vehicle base of the suppository given.17 20 21 In all three studies, lipophilic-based paracetamol suppositories were used. Four studies employed a single-dose design16 17 19 21 and four studies employed a multidose design.14 15 18 20 The surgery included abdominal, gynaecological and odontological procedures (Table 1).

In three trials of single-dose administration of rectal paracetamol 10–20 mg kg–1, no effect on pain scores or analgesic demand were observed16 17 19 compared with placebo. However, in the only trial of single-dose administration of rectal paracetamol 40 and 60 mg kg–1,17 pain scores and analgesic demand were significantly reduced in the early postoperative period, by approximately 21–34 mm on a VAS scale and 60–67% respectively. In contrast, no difference between study groups was observed in one trial comparing 20 and 40 mg kg–1 21 (Fig. 1).



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Fig 1 L’Abbé plots of mean visual analogue scale (VAS 0–100 mm) pain scores 1–8 h after surgery and of morphine consumption (µg kg–1 h–1) for rectal paracetamol (mg kg–1) vs placebo in trials for which data were available. Solid triangles: VAS score and morphine consumption were significantly (P<0.05) lower in the rectal paracetamol group compared with the placebo group. Solid squares: no significant difference in VAS scores or morphine consumption in the rectal paracetamol group compared with the placebo group.

 
In four trials of rectal paracetamol 14–20 mg kg–1 four times a day,14 15 18 20 pain scores were evaluated in three trials15 18 20 but were not significantly different between study groups in any of the studies (Fig. 1). However, supplementary analgesic consumption evaluated over 24–72 h periods was significantly reduced, by 16–36%, by rectal paracetamol (Fig. 1) in three14 15 20 of the four repeat dosing studies.14 15 18 20

No study evaluated time to first analgesic request.

In three studies, pain scores in the control groups were either low (VAS <30 mm)19 21 or the observation time was very short.16 19 Failure to detect analgesic effects of paracetamol may therefore have been the result of lack of sensitivity.19 21

Information about adverse effects was provided in seven studies1420 and no adverse effects attributable to rectal paracetamol were reported.

In summary, single doses of rectal paracetamol 10–20 mg kg–1 did not improve postoperative pain relief. However, single doses of rectal paracetamol 40–60 mg kg–1 did, in the only study available, significantly improve postoperative analgesia. Furthermore, in three of four studies, repeat dosing with rectal paracetamol 14–20 mg kg–1 was followed by a statistically and clinically significant reduction in analgesic consumption.

Parenteral paracetamol (propacetamol) versus placebo
Ten studies compared i.v.22 2633 or i.m.25 propacetamol 1 or 2 g (corresponding to paracetamol 0.5 g and 1 g respectively) with placebo (Table 2). Paracetamol was administered 1 h before surgery in one study33 and after surgery in nine studies.22 2532 Five studies employed a single-dose design22 25 26 29 30 and five used a multidose design.27 28 3133 The surgical procedures were orthopaedic, abdominal and odontological (Table 2).


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Table 2 Comparisons of parenteral paracetamol (propacetamol) with placebo. P<0.05=significant difference between parenteral paracetamol group and placebo group; n.s. = not significant;–= not evaluated; *calculated from demographic data
 
Pain scores were significantly lower in five of the 10 studies with parenteral paracetamol,22 25 26 29 30 with VAS reductions of 9–18 mm up to 4 h22 and 6 h29 after surgery (Fig. 2). In two of the studies with no difference in pain scores between treatment groups, patient-controlled morphine was administered as supplementary analgesia.28 32



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Fig 2 L’Abbé plot of mean VAS score 4–6 h after surgery for parenteral paracetamol (propacetamol) vs placebo in trials for which data were available. Solid triangles: VAS scores were significantly (P<0.05) lower in the parenteral paracetamol group compared with the placebo group. Solid squares: no significant difference in VAS scores in the parenteral paracetamol group compared with the placebo group.

 
Quantitative analysis of pain scores recorded 4–6 h after surgery was performed using a random effects model, as a test for heterogeneity was significant (P=0.0001). Eight studies were included in the analysis. In the two studies not included, one of which showed a reduced pain score,30 there was a lack of dispersion measures for the calculation.28 30 The analysis revealed a statistically significant overall WMD in VAS scores of –9 mm (95% confidence interval –16 to –2 mm) in favour of the parenteral paracetamol groups compared with the placebo groups (Fig. 3).



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Fig 3 Weighted mean difference (WMD) with 95% confidence intervals (95% CI, horizontal lines) in VAS scores 4–6 h after surgery between the parenteral paracetamol groups and the placebo groups in eight trials. References 26 and 28 were not included in the calculations because of lack of dispersion measures. ‘Total’ indicates the results of pooling all the trials. Numbers in the column headed ‘Weight’ indicate the weight of the individual trials in the analysis, taking into account study size and standard deviations of VAS scores.

 
Time to first analgesic request was evaluated in six studies2527 29 30 33 and was significantly increased, by about 38–119 min in the paracetamol groups,25 29 30 in only three studies.

Supplementary analgesic consumption was evaluated in six studies25 27 28 3133 and in four studies25 27 28 32 it was significantly reduced, by 36–50%, over periods of 625 and 24 h27 28 32 in the paracetamol groups compared with placebo. Adequate sensitivity was not guaranteed in one of the negative studies as VAS pain scores in the control group were less than 30 mm.33

Information about adverse effects was provided in eight studies.25 26 2833 In two studies, pain during infusion or at the injection site was reported in the propacetamol groups.29 30

In summary, of the 10 studies comparing parenteral paracetamol with placebo, eight 22 2530 32 showed improved pain relief after administration of parenteral propacetamol and quantitative analysis was statistically significant in favour of the treatment groups.

Comparisons of paracetamol given by different routes
Two studies compared parenteral with oral paracetamol and oral with rectal paracetamol respectively30 34 (Table 3). In the comparison of parenteral and oral administration, paracetamol 1 g was given after surgery in each study group. Pain scores were significantly lower up to 4 h after surgery and time to first analgesic request was significantly increased, by 34 min, in the parenteral group30 (Table 3). In the study comparing oral with rectal administration, 40 mg kg–1 of paracetamol elixir or suppositories was given 40 min preoperatively or after induction of anaesthesia respectively34 (Table 3). In the oral group, there was a significant reduction in pain score at 0.5 h (by approximately 20 mm on the VAS) and in analgesic demand over 4 h (by 57%).34


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Table 3 Comparisons of paracetamol given by different routes. P<0.05=significant difference between groups;–= not evaluated
 
Although results from these studies showed improved pain relief with parenteral compared with oral paracetamol and with oral compared with rectal paracetamol, the data are much too sparse for meaningful conclusions.

Comparisons of paracetamol with a combination of paracetamol and an NSAID
Nine studies compared paracetamol with a combination of paracetamol and an NSAID18 21 31 33 3741 (Table 4). Paracetamol 15–20 mg kg–1 18 21 33 39 or 0.5–1.5 g31 37 38 40 41 was administered in a single-dose21 37 3941 or multidose design.18 31 33 38 The NSAIDs were diclofenac 50–100 mg21 38 40 41 or 1 mg kg–1,18 ketoprofen 50 mg,31 ketorolac 0.5 mg kg–1,39 suprofen 100 mg37 and tenoxicam 0.5 mg kg–1,33 and were given as a single dose21 33 37 3941 or repeatedly.18 31 38 Paracetamol and NSAIDs were administered before surgery in five studies,18 21 33 39 40 after surgery in three studies31 38 41 and the day after surgery in one study.37 Further details of the studies are shown in Table 4. Pain scores were evaluated in seven studies. Four studies21 31 38 41 showed significantly lower pain scores after administration of the combination of paracetamol and an NSAID compared with paracetamol alone, with VAS reductions of 12–34 mm at 4 h21 and up to 8,41 1238 and 48 h31 after surgery (Fig. 4).


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Table 4 Comparisons of paracetamol with a combination of paracetamol and an NSAID. PCM=paracetamol; P<0.05=significant difference between PCM group and PCM plus NSAID group; n.s.=not significant;–= not evaluated
 


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Fig 4 L’Abbé plots of mean/median VAS scores 4–8 h after surgery and of morphine or tramadol consumption (mg per 24 h) for paracetamol vs paracetamol and an NSAID in trials for which data were available. Solid triangles: VAS scores and morphine consumption were significantly (P<0.05) lower in the paracetamol plus NSAID group compared with the paracetamol group. Solid squares: no significant difference in VAS scores and morphine consumption in the paracetamol plus NSAID group compared with the paracetamol group.

 
Time to first analgesic request was evaluated in only two studies.33 41 It was increased significantly, by 180 min, in the combination group in one study.41 In four studies,31 3941 supplementary analgesic consumption was significantly reduced, by 34–73% over periods of 8,41 24,39 40 and 48 h31 in the paracetamol and NSAID groups. In the five other trials, no difference between study groups was observed (Fig. 4).

Two of the negative studies were not considered adequately sensitive as VAS pain scores in the control groups were less than 30 mm.21 33

Information about adverse effects was provided in eight studies.18 31 33 3741 No adverse effects attributed to the concomitant administration of paracetamol and NSAIDs were reported.

In summary, of the nine studies comparing paracetamol with a combination of paracetamol and an NSAID, six21 31 3841 showed improved pain relief after administration of the combination.

Comparisons of an NSAID with a combination of an NSAID and paracetamol
Six studies compared an NSAID with a combination of an NSAID and paracetamol18 31 33 38 40 41 (Table 5). The NSAIDs were diclofenac 50–100 mg38 40 41 or 1 mg kg–1,18 ketoprofen 50 mg31 and tenoxicam 0.5 mg kg–1,33 administered as a single dose33 40 41 or with repeat dosing.18 31 38 Paracetamol 15–20 mg kg–1 18 33 or 0.5–1.5 g31 38 40 41 was given as a single dose40 41 or repeatedly.18 31 33 38 The NSAIDs and paracetamol were administered before surgery in three studies18 33 40 and after surgery in three studies.31 38 41 Further details of the studies are shown in Table 5.

Pain scores were significantly reduced after administration of the combination of the NSAID and paracetamol compared with the NSAID alone in two studies,31 41 with a VAS reduction of 11–29 mm up to 841 and 48 h31 after surgery. In the four other studies no difference was observed (Fig. 5).



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Fig 5 L’Abbé plots of mean/median VAS scores 4–8 h after surgery and of morphine or tramadol consumption (mg per 24 h) for an NSAID vs an NSAID and paracetamol in trials for which data were available. Solid triangles: VAS scores and morphine consumption were significantly (P<0.05) lower in the NSAID and paracetamol group compared with the NSAID group. Solid squares: no significant difference in VAS scores and morphine consumption in the NSAID and paracetamol group compared with the NSAID group.

 
Time to first analgesic request was evaluated in two studies33 41 but in only one study was it significantly increased (by 150 min) by the combination treatment.41 In one study, 41 supplementary analgesic consumption was significantly reduced (by 67%) over 8 h in the NSAID plus paracetamol group. In none of the other trials was analgesic demand different between study groups (Fig. 5). One study was not considered adequately sensitive as VAS scores in the control group were less than 30 mm.33 Information about adverse effects was provided in all six studies18 31 33 38 40 41 and no adverse effects attributed to the combination of NSAID and paracetamol were reported.

In summary, of the six studies comparing an NSAID with a combination of an NSAID and paracetamol, only two31 41 showed improved pain relief after administration of the combination.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Paracetamol is widely used for the management of perioperative pain. However, except for oral paracetamol, there is a marked discrepancy between the extent to which paracetamol is used and the available evidence for an analgesic effect in postoperative pain.

In order to clear up this discrepancy, we wanted to provide an evidence-based estimate of a clinical analgesic effect of rectal or parenteral paracetamol and of the combination of paracetamol and an NSAID compared with either drug alone in postoperative pain.

Surprisingly few eligible randomized studies were found. It was possible to perform a quantitative analysis of VAS pain scores with studies of parenteral paracetamol. In studies of rectal paracetamol and of combinations of paracetamol and an NSAID, lack of data allowed only a qualitative analysis. To describe data from original trials as thoroughly as possible, L’Abbé plots of VAS pain scores and the consumption of supplementary morphine were constructed.

Rectal paracetamol
There seems to be evidence for a clinically relevant analgesic effect of rectal paracetamol with an opioid-sparing effect comparable with that of NSAIDs. The rather high single doses of 40 and 60 mg kg–1 or repeat doses of paracetamol used in the four positive studies14 15 17 20 are likely to have led to a greater area under the curve for plasma paracetamol concentrations and therefore possibly greater efficacy over the study period than the single (lower) dose methods used in the four negative studies.16 18 19 21

The bioavailability of paracetamol suppositories is variable. It is approximately 80% of that of the tablets and the rate of absorption is slower, with maximum plasma concentrations achieved about 2–3 h after administration.45 This has to be taken into account in the dosing and timing of paracetamol in surgical patients. It is not optimal to administer rectal paracetamol at the induction of anaesthesia in procedures lasting only 0.5–1 h or to administer rectal paracetamol after surgery. Timing may have had an impact on the results in the negative studies. In clinical practice, it has to be taken into consideration that the vehicle base of the suppository has been shown to have an effect on the absorption of poorly soluble drugs such as paracetamol. A lipophilic base produces higher plasma paracetamol concentrations than a hydrophilic base.46 Information describing the vehicle base as lipophilic was provided in only three studies.17 20 21

Parenteral paracetamol
Propacetamol, an injectable prodrug of paracetamol, is completely hydrolysed within 6 min of administration and 1 g of propacetamol yields 0.5 g of paracetamol.25 Overall, results confirm a clinically relevant analgesic effect with parenteral paracetamol. The quantitative analysis of VAS scores was statistically significant in favour of the parenteral paracetamol groups and consumption of supplementary analgesics was significantly reduced, by 36–50%. Furthermore, in two of the positive studies,28 32 the use of morphine delivered by patient-controlled analgesia (PCA) may have resulted in the non-significant differences in pain scores between groups. This is consistent with the principle of PCA, in which the patient has the ability to provide satisfactory relief by increasing the cumulative dose of morphine. Finally, in one study, VAS pain scores in the control group were less than 30 mm and the negative findings may have been the result of pain after arthroscopy being a poor model for testing the efficacy of analgesics.33 Few adverse effects related to parenteral paracetamol were reported.29 30 However, because of the small number of studies included, no conclusions can be made.

The development of parenteral paracetamol has widened the range of possibilities for a well-tolerated drug being used in the postoperative period, when oral administration is prohibited. Propacetamol is marketed in several European countries.

Route of administration
We identified two studies in which a direct comparison was made between different routes of administration of the same dose of paracetamol in postoperative pain.30 34 Obviously, more studies are needed to test the evidence for any difference in analgesic efficacy of paracetamol given by different routes. Until such data are available, the route of administration in the postsurgical setting should probably depend on factors such as the presence or absence of gastrointestinal paralysis, nausea and vomiting and sedation.

Combinations of paracetamol and an NSAID
In clinical practice, paracetamol and an NSAID are often given in combination for acute postoperative pain. Concomitant administration of two analgesics with presumably different mechanisms of action may result in an additive analgesic effect. Data support the clinical practice of adding an NSAID to paracetamol to improve postoperative pain. On the other hand, no evidence was found for an improved analgesic effect by adding paracetamol to NSAIDs. The negative results may be related to the limited number of trials available; furthermore, adequate sensitivity was not guaranteed in two of the negative studies as VAS pain scores were less than 30 mm in the control groups.21 33 No adverse effects attributed to the combination of paracetamol and NSAIDs were reported. However, because of the small number of studies included, the data are insufficient to yield meaningful conclusions.

The conclusions from this systematic review may be considered to be rather tenuous because of the limited eligible data. There is therefore an urgent need for more well-designed large-scale studies, especially on the analgesic efficacy of repeated large rectal doses of paracetamol and on the combination of paracetamol and an NSAID. However, on the basis of the evidence available, we consider paracetamol given by any route to be an important basic analgesic drug in acute postoperative pain management.


    Acknowledgement
 
JBD was supported by a grant from the Danish Medical Research Council (no. 22000947).


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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