Combining Paracetamol (Acetaminophen) with Nonsteroidal Antiinflammatory Drugs: A Qualitative Systematic Review of Analgesic Efficacy for Acute Postoperative Pain : Anesthesia & Analgesia

Secondary Logo

Journal Logo

Pain Medicine: Research Reports

Combining Paracetamol (Acetaminophen) with Nonsteroidal Antiinflammatory Drugs

A Qualitative Systematic Review of Analgesic Efficacy for Acute Postoperative Pain

Ong, Cliff K. S. PhD*; Seymour, Robin A. PhD; Lirk, Phillip MD; Merry, Alan F. MBChB, FANZCA, FPMANZCA, FRCA§

Editor(s): Liu, Spencer S.

Author Information
Anesthesia & Analgesia 110(4):p 1170-1179, April 2010. | DOI: 10.1213/ANE.0b013e3181cf9281

Different classes of analgesics exert their effects through different mechanisms. Their side effects (e.g., respiratory depression with opioids or enteropathy with nonsteroidal antiinflammatory drugs [NSAIDs]) tend to be different and may be dose related. A combination of analgesics from different classes may provide additive analgesic effects with fewer side effects than when a single therapeutic drug is used. There has been a trend over recent years for combining NSAIDs with paracetamol (acetaminophen) for the management of acute postoperative pain,1,2 but the therapeutic superiority of the combination over either drug alone remains controversial.3,4 In 2002, Hyllested et al.5 noted that paracetamol/NSAID combinations showed superior pain relief over paracetamol alone in 5 of 7 studies, but over an NSAID alone in only 2 of 4 studies, whereas Rømsing et al.2 noted an advantage for such combinations over paracetamol alone in 6 of 9 studies but over an NSAID alone in only 2 of 6 studies. These authors noted that relevant studies were sparse. We have updated these reviews to include randomized controlled trials (RCTs) published since then with the aim of evaluating whether paracetamol/NSAID combinations provide superior efficacy in the treatment of acute postoperative pain to either drug alone.


We aimed to determine whether paracetamol/NSAID combinations provide superior efficacy in the treatment of acute postoperative pain to either drug alone.


A broad free-text search restricted to RCTs in English was undertaken in Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and PubMed, from January 1988 to June 2009. The full reports were retrieved for double-blind RCTs comparing paracetamol/NSAID combinations with 1 or both of their constituent drugs for pain relief. Variants of the search terms including “paracetamol/NSAIDs combination,” “acetaminophen,” “combination analgesics,” “acute postoperative pain,” and “ibuprofen/paracetamol” or individual drug names were entered as major subject headings. Reference lists of retrieved publications were checked for additional trials.

Exclusion criteria were (1) comparison of a paracetamol/ NSAID combination with analgesics other than paracetamol or NSAIDs, (2) other pain models, e.g., chronic pain, and (3) retrospective, nonrandomized, or nonblinded trials. The retrieved reports were stratified according to the NSAID in the combination, the mode of administration (oral, IM, IV, rectal), and the surgical procedures studied.

Where possible, data on the following outcome measures were extracted from the retrieved publications in the form of mean/median and assessed for reported differences between the combination and constituent drug groups:

  1. Pain intensity in the form of pain scores, e.g., postoperative visual analog scale (VAS) scores.
  2. Supplemental postoperative analgesic requirements, e.g., opioid consumption.

In cases in which results of trials were reported only in graphical form, the means and SDs were estimated from these graphs. The difference in analgesic response among the study groups, i.e., % difference in pain intensity and % difference in analgesic supplementation, was extracted from the studies or calculated from the studies whenever possible. The mean/SD of the difference in analgesic response of all the positive studies was calculated.

Each study was graded for quality, using the validated scale of Jadad et al.,6 on the extent to which its design, data collection, and statistical analysis minimized or avoided bias as follows:

  1. Randomization: If the reports were described as randomized, 1 point was given. An additional point was given if the method of randomization was described and adequate (e.g., using computer-generated or table of random numbers). One point was deducted if the method of randomization was inappropriate (e.g., randomization according to age or birthdays).
  2. Blinding: If the reports were described as double blind, 1 point was given. An additional point was given if the method of blinding was described and appropriate (e.g., use of double dummy). One point was deducted if the method of blinding was inappropriate.
  3. Patients' withdrawals: If the reports described the numbers and reasons for withdrawals, 1 point was given.

The possible range for these scores in the included studies was 2 to 5. A Mann-Whitney U test was used to assess the relationships between the positive and negative trials and the quality scores. Subgroup analyses were performed for the combination versus paracetamol and combination versus NSAID by surgical model and by NSAID.

Statistical heterogeneity across the studies was evaluated both qualitatively and quantitatively using the funnel plot and Cochran Q test, respectively. The computer software package, SPSS for Windows (SPSS, Chicago, IL), and Comprehensive Meta-Analysis™ (Biostat, Englewood, NJ) were used.


Thirty-two studies that evaluated paracetamol/NSAID combinations were found.738 Eleven were excluded because of inadequate randomization, nonblinding, or comparison of the combinations with different classes of analgesics or studies in chronic pain.717 Twenty-one RCTs in acute postoperative pain models with a total of 1909 patients were included for further analysis.1838

Studies comparing paracetamol/NSAID combinations with paracetamol alone are summarized in Table 1, and those comparing paracetamol/NSAID combinations with NSAIDs alone are summarized in Table 2.

Table 1:
Studies of Paracetamol/Nonsteroidal Antiinflammatory Drugs (NSAID) Combinations Versus Paracetamol Alone
Table 2:
Studies of Paracetamol/Nonsteroidal Antiinflammatory drugs (NSAID) Combinations Versus NSAIDs Alone

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)19,31,32,3436; 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 paracetamol2022,2426,29,31,32,34,3638; 20 compared the combination with paracetamol alone1829,3138 (Table 1); and 14 compared the combination with an NSAID alone (Table 2).2022,2426,2932,34,3638

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%).19,31,32,3436 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.

Figure 1:
Funnel plot of the treatment effect against a measure of study size for studies of paracetamol/nonsteroidal antiinflammatory drug combinations versus paracetamol alone.

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.

Figure 2:
Funnel plot of the treatment effect against a measure of study size for studies of paracetamol/nonsteroidal antiinflammatory drug (NSAID) combinations versus NSAID alone.

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.3,4,3945 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.4654 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.5659 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.5759 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.6163 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.


1. Merry A, Power I. Perioperative NSAIDs: towards greater safety. Pain Rev 1995;2:268–91
2. Rømsing J, Møiniche S, Dahl JB. Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia. Br J Anaesth 2002;88:215–26
3. Ong CKS, Seymour RA. An evidence-based update of the use of analgesics in dentistry. Periodontol 2000 2008;46:143–64
4. Ong CKS, Lirk P, Tan CH, Seymour RA. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res 2007;5:19–34
5. Hyllested M, Jones S, Pedersen JL, Kehlet H. Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth 2002;88:199–214
6. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12
7. Davie IT, Gordon NH. Comparative assessment of fenoprofen and paracetamol given in combination for pain after surgery. Br J Anaesth 1978;50:931–5
8. Man CY, Cheung IT, Cameron PA, Rainer TH. Comparison of oral prednisolone/paracetamol and oral indomethacin/ paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial. Ann Emerg Med 2007;49:670–7
9. Mehtani A, Shersia A, Singh S, Salve JK. Efficacy of a fixed dose combination of diclofenac sodium and acetaminophen (Rhumacort) injection in postoperative pain. J Indian Med Assoc 2006;104:200–3
10. Merry AF, Swinburn PF, Middleton NG, Edwards JL, Calder MV. Tenoxicam and paracetamol-codeine combination after oral surgery: a prospective, randomized, double-blind, placebo-controlled study. Br J Anaesth 1998;81:875–80
11. Mitchell A, van Zanten SV, Inglis K, Porter G. A randomized controlled trial comparing acetaminophen plus ibuprofen versus acetaminophen plus codeine plus caffeine after outpatient general surgery. J Am Coll Surg 2008;206:472–9
12. Raff M. The usage and efficacy of a combination analgesic preparation. S Afr J Anesth Analg 2002;8:34–8
13. Roy IS, Das A, Roy M. A comparative study of ibuprofen with paracetamol versus oxyphenbutazone with analgesic combination in ophthalmic practice. Indian J Opthalmol 1988;36:37–40
14. Seideman P, Samuelson P, Neander G. Naproxen and paracetamol compared with naproxen only in coxarthrosis: increased effect of the combination in 18 patients. Acta Orthop Scand 1993;64:285–8
15. Seideman P. Equianalgesic effects of paracetamol and indomethacin for rheumatoid arthritis. Br J Rheumatol 1988;27:117–22
16. Vanlacker P, Cooman F. The analgesic effect of preoperative administration of propacetamol, tenoxicam or a mixture of both in arthroscopic outpatient knee surgery. Acta Anaesthesiol Belg 1999;50:65–9
17. Vlok GJ, van Vuren JP. Comparison of a standard ibuprofen treatment regimen with a new ibuprofen/paracetamol/codeine combination in chronic osteo-arthritis. S Afr Med J 1987;17(suppl 1):4–6
18. Aubrun F, Langeron O, Heitz D, Coriat P, Riou B. Randomised, placebo-controlled study of the postoperative analgesic effects of ketoprofen after spinal fusion surgery. Acta Anaesthesiol Scand 2000;44:934–9
19. Beck DH, Schenk MR, Hagemann K, Doepfmer UR, Kox WJ. The pharmacokinetics and analgesic efficacy of larger dose rectal acetaminophen (40 mg/kg) in adults: a double-blinded, randomized study. Anesth Analg 2000;90:431–6
20. Breivik EK, Barkvoll P, Skovlund E. Combining diclofenac with acetaminophen or acetaminophen-codeine after oral surgery: a randomized, double-blind single-dose study. Clin Pharmacol Ther 1999;66:625–35
21. Dahl V, Dybvik T, Steen T, Aune AK, Rosenlund EK, Raeder JC. Ibuprofen vs. acetaminophen vs. ibuprofen and acetaminophen after arthroscopically assisted anterior cruciate ligament reconstruction. Eur J Anaesthesiol 2004;21:471–5
22. Fletcher D, Nègre I, Barbin C, François A, Carreres C, Falgueirettes C, Barboteu A, Samii K. Postoperative analgesia with i.v. propacetamol and ketoprofen combination after disc surgery. Can J Anaesth 1997;44:479–85
23. Gazal G, Mackie IC. A comparison of paracetamol, ibuprofen or their combination for pain relief following extractions in children under general anaesthesia: a randomized controlled trial. Int J Paediatr Dent 2007;17:169–77
24. Haglund B, von Bültzingslöwen I. Combining paracetamol with a selective cyclooxygenase-2 inhibitor for acute pain relief after third molar surgery: a randomized, double-blind, placebo-controlled study. Eur J Oral Sci 2006;114:293–301
25. Hiller A, Meretoja OA, Korpela R, Piiparinen S, Taivainen T. The analgesic efficacy of acetaminophen, ketoprofen, or their combination for pediatric surgical patients having soft tissue or orthopedic procedures. Anesth Analg 2006;102:1365–71
26. Hiller A, Silvanto M, Savolainen S, Tarkkila P. Propacetamol and diclofenac alone and in combination for analgesia after elective tonsillectomy. Acta Anaesthesiol Scand 2004;48:1185–9
27. Ianiro SR, Jeansonne BG, McNeal SF, Eleazer PD. The effect of preoperative acetaminophen or a combination of acetaminophen and ibuprofen on the success of inferior alveolar nerve block for teeth with irreversible pulpitis. J Endod 2007;33:11–4
28. Mather SJ, Peutrell JM. Postoperative morphine requirements, nausea and vomiting following anaesthesia for tonsillectomy. Comparison of intravenous morphine and non-opioid analgesic techniques. Paediatr Anaesth 1995;5:185–8
29. Matthews RW, Scully CM, Levers BG. The efficacy of diclofenac sodium (Voltarol) with and without paracetamol in the control of post-surgical dental pain. Br Dent J 1984;157:357–9
30. Menhinick KA, Gutmann JL, Regan JD, Taylor SE, Buschang PH. The efficacy of pain control following nonsurgical root canal treatment using ibuprofen or a combination of ibuprofen and acetaminophen in a randomized, double-blind, placebo-controlled study. Int Endod J 2004;37:531–41
31. Montgomery JE, Sutherland CJ, Kestin IG, Sneyd JR. Morphine consumption in patients receiving rectal paracetamol and diclofenac alone or in combination. Br J Anaesth 1996;77:445–7
32. Munishankar, Fettes P, Moore C, McLeod GA. A double-blind randomized controlled trial of paracetamol, diclofenac or the combination for pain relief after caesarean section. Int J Obstet Anesth 2008;17:9–14
33. Pickering AE, Bridge HS, Nolan J, Stoddart PA. Double-blind, placebo-controlled analgesic study of ibuprofen or rofecoxib in combination with paracetamol for tonsillectomy in children. Br J Anaesth 2002;88:72–7
34. Riad W, Moussa A. Pre-operative analgesia with rectal diclofenac and/or paracetamol in children undergoing inguinal hernia repair. Anaesthesia 2007;62:1241–5
35. Rubin A, Winter L Jr. A double-blind randomized study of an aspirin/caffeine combination versus acetaminophen/aspirin combination versus acetaminophen versus placebo in patients with moderate to severe post-partum pain. J Int Med Res 1984;12:338–45
36. Siddik SM, Aouad MT, Jalbout MI, Rizk LB, Kamar GH, Baraka AS. Diclofenac and/or propacetamol for postoperative pain management after cesarean delivery in patients receiving patient controlled analgesia morphine. Reg Anesth Pain Med 2001;26:310–5
37. Vanlanker P, Vanderkeckhove B, Cooman F. The analgesic effect of preoperative propacetamol, tenoxicam or a mixture of both for arthroscopic knee surgery. Acta Anaesthsiol Belg 1999;50:65–9
38. Viitanen H, Tuominen N, Vääräniemi H, Nikanne E, Annila P. Analgesic efficacy of rectal acetaminophen and ibuprofen alone or in combination for paediatric day-case adenoidectomy. Br J Anaesth 2003;91:363–7
39. Seideman P. Additive effect of combined naproxen and paracetamol in rheumatoid arthritis. Br J Rheumatol 1993;32:1077–82
40. Curatolo M, Sveticic G. Drug combinations in pain treatment—a review of the published evidence and a method for finding the optimal combination. Best Pract Res Clin Anaesthesiol 2002;16:507–19
41. Mehlisch DR. The efficacy of combination analgesic therapy in relieving dental pain. J Am Dent Assoc 2002;133:861–71
42. Lange H, Kranke P, Steffen P, Steinfeldt T, Wulf H, Eberhart LH. Combined analgesics for postoperative pain therapy. Review of effectivity and side-effects. Anaesthesist 2007;56:1001–16
43. Demeules J, Rollasen V, Piguet V, Dayer P. Clinical pharmacology and rationale of analgesic combinations. Eur J Anaesthesiol Suppl 2003;28:7–12
44. Rafa RB. Pharmacology of oral combination analgesics: rational therapy for pain. J Clin Pharm Ther 2001;26:257–64
45. World Health Organization. Cancer Pain Relief and Palliative Care: Report of a WHO Expert Committee. Geneva: World Health Organization, 1990:7–21
46. Henry D, Lim LL, Garcia Rodriguez LA, Perez Gutthann S, Carson JL, Griffin M, Savage R, Logan R, Moride Y, Hawkey C, Hill S, Fries JT. Variability in risk of major upper gastrointestinal complications with individual NSAIDs: results of a collaborative meta-analysis. BMJ 312:1563–6
47. Henry D, McGettigan P. Epidemiology overview of gastrointestinal and renal toxicity of NSAIDs. Int J Clin Pract Suppl 2003;135:43–9
48. Kellstein DE, Waksman JA, Furey SA, Binstok G, Cooper SA. The safety profile of non-prescription ibuprofen in multiple dose use: a meta-analysis. J Clin Pharmacol 1999;39:520–3
49. MacDonald TM, Morant SV, Robinson GC, Shield MJ, McGilchrist MM, Murray FE, McDevitt DG. Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study. Br Med J 1997;315:1333–7
50. Garcia Rodriguez LA, Cattaruzzi C, Troncon MG, Agostinis L. Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs. Arch Intern Med 1998;158:33–9
51. Doyle G, Furey S, Berlin R, Cooper S, Jayawardena S, Ashraf E, Baird L. Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counter dose. Aliment Pharmacol Ther 1999;13:897–906
52. Griffin MR, Yared A, Ray WA. Nonsteroidal anti-inflammatory drugs and acute renal failure in elderly persons. Am J Epidemiol 2000;151:488–96
53. Lesko SM, Mitchell AA. The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics 1999;104:e39
54. Moore N, Vanganse E, Leparc J-M, Wall R, Schneid H, Farhan M, Verrière F, Pelen F. A large-scale, randomised clinical trial comparing the tolerability of aspirin, ibuprofen and paracetamol for short-term analgesia. Clin Drug Invest 1999;18:89–98
55. Wolfe MM, Lichtensein DR, Singh G. Medical progress: gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 1999;340:1888–99
56. Gray A, Kehlet H, Bonnet F, Rawal N. Predicting postoperative analgesia outcomes: NNT league tables or procedure-specific evidence? Br J Anaesth 2005;94:710–4
57. Barden J, Edwards JE, McQuay HJ, Moore A. Pain and analgesic response after third molar extraction and other postsurgical pain. Pain 2004;107:86–90
58. Edwards JE, Oldman AD, Smith LA, Carroll D, Wiffen PJ, McQuay HJ, Moore RA. Oral aspirin in postoperative pain: a quantitative systematic review. Pain 1999;81:289–97
59. Hargreaves KM. Legitimate to extrapolate efficacy from one pain context to another. Evid Based Dent 2004;5:42
60. Collins SL, Moore RA, McQuay HJ. The visual analogue pain scale: what is moderate pain in millimeters. Pain 1997;72:95–7
61. Miranda HF, Puig MM, Prieto JC, Pinardi G. Synergism between paracetamol and nonsteroidal anti-inflammatory drugs in experimental acute pain. Pain 2006;121:22–8
62. Qiu HX, Liu J, Kong H, Liu Y, Mei XG. Isobolographic analysis of the antinociceptive interactions between ketoprofen and paracetamol. Eur J Pharmacol 2007;557:141–6
63. Miranda HF, Prieto JC, Puig MM, Pinardi G. Isobolographic analysis of multimodal analgesia in an animal model of visceral acute pain. Pharmacol Biochem Behav 2008;88:481–6
64. Hayashi G, Takemori AE. The type of analgesic receptor interaction involved in certain analgesic assays. Eur J Pharmacol 1971;16:63–6
© 2010 International Anesthesia Research Society