The evaluated NSAIDs were ibuprofen (n = 6),21,23,27,30,33,38 diclofenac (n = 8),19,20,26,29,31,32,34,36 ketoprofen (n = 3),18,22,25 ketorolac (n = 1),28 aspirin (n = 1),35 tenoxicam (n = 1),37 and rofecoxib (n = 1).24 The models studied were dental surgery (n = 6)20,23,24,27,29,30; orthopedic surgery (n = 5)18,21,22,25,37; gynecological/inguinal surgery (n = 6)19,31,32,34–36; and ear, nose, and throat (ENT) surgery (n = 4).26,28,33,38 Of these, 13 compared the effect of the combination with both an NSAID and paracetamol20–22,24–26,29,31,32,34,36–38; 20 compared the combination with paracetamol alone18–29,31–38 (Table 1); and 14 compared the combination with an NSAID alone (Table 2).20–22,24–26,29–32,34,36–38
Results for Studies of a Combination Versus Paracetamol Alone
Twenty studies involving 1852 patients compared the efficacy of an analgesic combination with paracetamol alone (Table 1). Overall, 17 of these 20 studies (85%) showed that the combination was more effective than paracetamol alone in terms of lower pain scores, lower supplemental analgesic requirements, or better globally assessed pain relief (positive studies). For surgical model subgroup analysis, the ENT model had positive results for all 4 studies (100%)26,28,33,38; the dental model had 4 of 5 positive studies (80%)20,23,24,27,29; the orthopedic model had 4 of 5 positive studies (80%)18,21,22,25,37; and the gynecological/inguinal model had 5 of 6 positive studies (83%).19,31,32,34–36 For NSAID subgroup analysis, all 5 ibuprofen studies showed consistently positive results (100%)21,23,27,30,33,38; the diclofenac studies had 6 of 8 positive results (75%)19,20,26,29,31,32,34,36; the 3 ketoprofen studies all showed positive results (100%)18,22,25; and the single rofecoxib, ketorolac, and aspirin studies each showed positive results.24,28,35 However, the single tenoxicam combination study showed no difference in analgesic efficacy compared with paracetamol alone.37
Overall, mean (SD) reduction in pain intensity was 35.0% (10.9%); the reduction in analgesic supplementation was 38.8% (13.1%). The quality scores of the studies ranged from 2 to 5. The median quality score was 4 for the positive studies and 3 for the negative studies (Mann-Whitney U test: P = 0.18).
Figure 1 is a funnel plot of the included studies for the treatment effect against a measure of study size. The asymmetric funnel suggests the possibility of a systematic difference between smaller and larger studies or systematic heterogeneity. In addition, a test of statistical heterogeneity yielded a highly significant result (Q value = 38.4, df(Q) = 18, P = 0.003), giving substantial evidence of statistical heterogeneity. The results of these heterogeneity tests further add legitimacy for the appropriateness of a qualitative over quantitative systematic review for these studies.
Results for Studies of a Combination Versus NSAIDs Alone
Fourteen studies involving 1129 patients compared the efficacy of an analgesic combination with an NSAID alone (Table 2). Overall, 9 of these 14 studies (64%) showed that the combination was more effective than an NSAID alone in terms of lower pain scores, lower supplemental analgesic requirements, or better globally assessed pain relief for the combination group. For surgical model subgroup analysis, the ENT model showed positive results for both studies (100%)26,38; the dental model had 3 of 4 positive studies (75%)20,24,29,30; the orthopedic model had 2 of 4 positive studies (50%)21,22,25,37; and the gynecological model had 2 of 4 positive studies (50%).31,32,34,36 For the NSAID subgroup analysis, the ibuprofen studies had 2 of 3 positive results (67%)21,30,38; the diclofenac studies had 4 of 7 positive results (57%)20,26,29,31,32,34,36; both the ketoprofen studies had positive results (100%)22,25; and the single rofecoxib combination study showed positive results.24 However, the single tenoxicam combination study showed no difference in analgesic efficacy compared with an NSAID alone.37
Overall, the mean (SD) reduction in pain intensity was 37.7% (26.6%); the reduction in analgesic supplementation was 31.3% (13.4%). The quality scores for the studies ranged from 3 to 5. The median value for the positive studies was 5 and 4 for the negative studies (Mann-Whitney U test: P = 0.39).
Figure 2 is a funnel plot of the included studies for the treatment effect against a measure of study size. Once again, the asymmetric funnel suggests the presence of systematic heterogeneity. In addition, a test of statistical heterogeneity yielded a highly significant result (Q value = 35.4, df(Q) = 13, P = 0.002), giving substantial evidence of statistical heterogeneity.
There was no evidence of an increased incidence of side effects with combinations compared with individual drugs alone. Most studies reported no difference between the side effect profiles with combination therapy versus single-drug therapy. The incidence of nausea and vomiting was significantly higher in some studies for the single-therapy groups that required more morphine as rescue medication.19,31 In general, adverse effects were mild and infrequent in all the studies, and mostly related to known side effects of the investigated drugs. The most common side effects reported were nausea, vomiting, drowsiness, and headache (Tables 1 and 2). There were no serious adverse effects reported for any of the combination analgesics tested in combination or alone.
This review suggests that combining paracetamol and an NSAID confers additional analgesic efficacy over either drug alone. The combination of paracetamol and an NSAID was more effective than paracetamol or an NSAID alone in 85% and 64% of the studies, respectively. The subgroup analysis by surgical model and NSAID type confirms our overall results and further strengthens our conclusion. This conclusion is consistent with many previous expert reviews that recommend the use of combination analgesics.3,4,39–45 The recommendations from most of the previous expert reviews were based on logic rather than evidence, and in this review, we have attempted to provide the evidence.
Overall, ibuprofen was one of the NSAIDs most widely evaluated in the studies reviewed. The value of combining it with paracetamol was confirmed in all of the 5 studies against paracetamol alone,21,23,27,30,33,38 and 2 of the 3 studies against an NSAID alone.21,30,38 Ibuprofen has a well-established reputation for safety and efficacy compared with other NSAIDs.46–54 However, even with ibuprofen, the risks are a function of the dose and duration of use.55 Hence, the case for combining ibuprofen with paracetamol to obtain increased analgesia without increasing the dose of the NSAID is strong.
Limitations of our study include its qualitative approach and the wide range of acute pain models included in the studies reviewed.56 We note continuing debate over combining of different surgical models in acute pain studies.56–59 A commentary criticized combining results from different surgical models in pain studies on the basis of comparisons of relative risk and seeking aid from the dubious ally of heterogeneity tests.56 The authors argued that different models of acute pain may well produce different outcomes on the basis of the results for paracetamol 975/1000 mg in acute pain trials. On the contrary, there are at least 2 systematic reviews and 1 commentary that suggest that there is little difference between the different acute surgical models in the estimate of analgesic efficacy.57–59 A quantitative meta-analysis would certainly not be possible for the included RCTs in this review because of heterogeneity of study design. Our subgroup analysis by surgical model provides considerable reassurance in relation to any influence of this heterogeneity on our overall qualitative findings.
Some of the negative studies included in this review may not have adequate sensitivity to detect a difference in pain scores between groups because the VAS pain scores were relatively low in the control groups. Moderately severe pain (e.g., VAS score >30 mm) is required in pain studies to achieve adequate sensitivity because it may not be possible to detect any difference if there is little or no pain.60 The mean pain scores in the control groups were ≤30 mm in 4 of the 5 negative studies that compared the combination with NSAIDs.21,29,31,32,37 In all 4 studies, the analgesics were given preemptively, either before surgery or immediately after surgery before pain developed.21,29,31,37 In addition, it should be noted that some studies with small group sizes may not have adequate power to detect a difference even if present.21,29,31,32,37
Three recent animal studies also provide evidence in favor of combinations of paracetamol and NSAIDs for analgesia.61–63 All 3 studies used the mouse acetic acid abdominal constriction test, a validated pain model in rodents, to measure analgesic effect of drug combinations.64 Miranda et al.61 compared antinociception induced by the intraperitoneal coadministration of combinations of paracetamol with the widely used NSAIDs diclofenac, ibuprofen, ketoprofen, meloxicam, metamizol, naproxen, nimesulide, parecoxib, and piroxicam. They concluded that all of the combinations were synergistic. Qiu et al.62 and Miranda et al.63 investigated the antinociceptive effect of oral paracetamol and ketoprofen alone or in combination and the antinociceptive effect of intraperitoneal administration of paracetamol, ketoprofen, and morphine alone or in combination, respectively. Similar dose-response curves were obtained in these 2 animal studies in favor of adding an NSAID to paracetamol.
There are some potential disadvantages in combining NSAIDs and paracetamol. A combination may be disadvantageous when individual drugs are specifically suited to a patient's symptoms (e.g., when only the antipyretic action of paracetamol is required for fever). Combining analgesics may increase the incidence of adverse effects. The use of fixed-dose combinations may reduce flexibility in dose titration, or conversely may expose patients to unnecessarily large doses of NSAIDs with consequent adverse effects, particularly in susceptible patients. Furthermore, combinations will not be suitable for patients with contraindications to either drug alone. For example, paracetamol should be used with caution (if at all) in patients with preexisting liver disease, whereas a history of gastrointestinal ulcers or renal impairment precludes use of traditional NSAIDs. The combination of paracetamol and long-acting NSAIDs such as tenoxicam has the theoretical disadvantage of pharmacokinetic incompatibility because tenoxicam has a much longer elimination half-life than paracetamol.
We conclude that a combination of acetaminophen and NSAIDs may provide superior analgesia than either drug alone.
Dr. Merry's unit has received grants from AFT Pharmaceuticals Ltd for research into a combination of paracetamol and ibuprofen.
The authors acknowledge with thanks secretarial assistance from Dr. Jennifer Zhang of AFT Pharmaceuticals Ltd.
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