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Open Access

Peer-reviewed

Research Article

The Efficacy and Clinical Safety of Various Analgesic Combinations for Post-Operative Pain after Third Molar Surgery: A Systematic Review and Meta-Analysis

  • Alvin Ho Yeung Au,

    Affiliation Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong Special Administrative Region, People Republic of China

    ⨯
  • Siu Wai Choi,

    Affiliation Laboratory and Clinical Research Institute for Pain, Department of Anaesthesiology, Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People Republic of China

    ⨯
  • Chi Wai Cheung,

    Affiliation Laboratory and Clinical Research Institute for Pain, Department of Anaesthesiology, Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People Republic of China

    ⨯
  • Yiu Yan Leung

    mikeyyleung@hku.hk

    Affiliation Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong Special Administrative Region, People Republic of China

    ⨯

Abstract

Objectives

To run a systematic review and meta-analysis of randomized clinical trials aiming to answer the clinical question “which analgesic combination and dosage is potentially the most effective and safe for acute post-operative pain control after third molar surgery?”.

Materials and Methods

A systematic search of computer databases and journals was performed. The search and the evaluations of articles were performed by 2 independent reviewers in 3 rounds. Randomized clinical trials related to analgesic combinations for acute post-operative pain control after lower third molar surgery that matched the selection criteria were evaluated to enter in the final review.

Results

Fourteen studies with 3521 subjects, with 10 groups (17 dosages) of analgesic combinations were included in the final review. The analgesic efficacy were presented by the objective pain measurements including sum of pain intensity at 6 hours (SPID6) and total pain relief at 6 hours (TOTPAR6). The SPID6 scores and TOTPAR6 scores of the reported analgesic combinations were ranged from 1.46 to 6.44 and 3.24 – 10.3, respectively. Ibuprofen 400mg with oxycodone HCL 5mg had superior efficacy (SPID6: 6.44, TOTPAR6: 9.31). Nausea was the most common adverse effect, with prevalence ranging from 0-55%. Ibuprofen 200mg with caffeine 100mg or 200mg had a reasonable analgesic effect with fewer side effects.

Conclusion

This systematic review and meta-analysis may help clinicians in their choices of prescribing an analgesic combination for acute post-operative pain control after lower third molar surgery. It was found in this systematic review Ibuprofen 400mg combined with oxycodone HCL 5mg has superior analgesic efficacy when compared to the other analgesic combinations included in this study.

Citation: Au AHY, Choi SW, Cheung CW, Leung YY (2015) The Efficacy and Clinical Safety of Various Analgesic Combinations for Post-Operative Pain after Third Molar Surgery: A Systematic Review and Meta-Analysis. PLoS ONE 10(6): e0127611. https://doi.org/10.1371/journal.pone.0127611

Academic Editor: Francesco Staffieri, University of Bari, ITALY

Received: December 17, 2014; Accepted: April 17, 2015; Published: June 8, 2015

Copyright: © 2015 Au et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: The authors have no support or funding to report.

Competing interests: The authors have declared that no competing interests exist.

Introduction

The combination of analgesics from different classes may provide additive analgesic effects with lesser side effects than when a single drug is used [1, 2]. It has also been suggested that the combination of analgesics can provide different mechanisms of action and therefore multimodal coverage of a wider spectrum of pain, thus enable the drug components to provide potential synergistic effect [3]. Moreover, in terms of safety, analgesic combinations may allow a lower dose of single drug component, which may result in a lower incidence of adverse effects. As multiple pathways of human body’s nociception were suggested [4], analgesic combinations are appropriate for pain management and has been recommended by World Health Organization (WHO) [5], the American Pain Society (APS) [6] and the American College of Rheumatology (ACR) [7].

Acute post-operative dental pain model has been suggested as an excellent analgesic model because the pain can be debilitating [8]. Wisdom tooth surgery has been commonly used in studies to investigate the efficacy of single or combination analgesics [9–11]. Review of the literature demonstrated that analgesic combinations of NSAIDs or acetaminophen and opioids were superior to single drug in terms of analgesic effect and/ or side-effect for acute post-operative pain [12].

However, among the enormous number of possible combinations, there is a lack of knowledge regarding which therapeutic analgesic combination and the respective drug dosages is more superior in terms of analgesic efficacy and its clinical safety. Therefore the purpose of the study was to conduct a systematic review and meta-analysis to answer a clinical question “which analgesic combination and dosage is potentially the most effective and safe for acute post-operative pain control after third molar surgery?”

Materials and Methods

A systematic review and meta-analysis was designed to perform two rounds of comprehensive searches of literature with relevance to the clinical question and a round of critical evaluation to identify relevant articles that could be included in the final review. Two authors (A.H.Y. and L.Y.Y.) were judges in the two rounds of search and the evaluation round, and worked independently according to the protocol and were blinded to each other’s choice. Disagreements between two judges were discussed and solved by consent. A third party (N.S.) was consulted if any consensus to a disagreement could not be reached.

First round search

Three databases (Pubmed, Embase and the Cochrane Library) were searched. There were no restriction criteria set on language or publication date. The last date of the search was 1st March, 2013. The electronic search was performed using the keywords:

  1. third molar;
  2. wisdom tooth;
  3. dentoalveolar surgery
  4. analgesic
  5. painkiller
  6. acute dental pain
  7. combination

A search was performed by (1 or 2 or 3) AND (4 or 5 or 6 or 7)

A list of articles with the search strategy was generated. Each abstract of the articles was reviewed. The full articles were retrieved if there was inadequate information in the abstracts or the abstracts were missing. Articles relevant to the study of analgesics combination and third molar surgery were selected and included in the next round.

Second round search and selection

To expand the search for possible articles that were relevant to the topic, a manual search was performed on three international oral and maxillofacial surgery journals (Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology; International Journal of Oral and Maxillofacial Surgery; and Journal of Oral and Maxillofacial Surgery). The manual search of these 3 journals was limited to the period from March 2003 to Feb 2013. Articles relevant to the treatment of post-operative dental pain and uses of combination analgesia were selected in this round.

A reference list search was performed from the manual search articles and the selected articles of the first round articles. Articles that were relevant to the study of post-operative dental pain and combination of analgesic efficacy and clinical safety were selected.

In addition to the articles from the first round, all articles were evaluated. Two independent judges (A.H.Y and L.Y.Y) carried out independent selection of the articles entered this round, according to the following selection criteria:

  1. Articles must be limited to third molar surgery;
  2. Articles must be limited for assessing the combination of analgesic;
  3. Articles must be randomized clinical trials.

Articles had to fulfill all these three criteria to be selected to enter the third round evaluation.

Third round evaluation

Articles entering the third round were evaluated by two independent judges (A.H.Y and L.Y.Y) based on the following criteria.

  1. The study must contain one or more of the following information about the patients who underwent wisdom tooth surgery: basic demographic data (mean age, gender of patients); number of wisdom teeth removed; and baseline pain intensity.
  2. The study must contain a placebo group.
  3. The articles must consist of the following two objective pain measurements that were commonly used in analgesic studies:
    • Sum of pain intensity difference in 6 hours (SPID6);
    • Total pain relief in 6 hours (TOTPAR6).
  4. The articles must include the adequate description on the side effect, patient tolerability and safety of the drugs.

Articles had to fulfill all criteria to be included in the final review. Table 1 summarized the eligibility criteria for articles included in the final review. Table 2 listed the excluded studies and the reasons for exclusion.

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Table 1. Eligibility criteria for articles included in the final review.

https://doi.org/10.1371/journal.pone.0127611.t001

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Table 2. Excluded studies at the third round and explanation for exclusion.

https://doi.org/10.1371/journal.pone.0127611.t002

Final review

Articles entering the final review were being assessed of the efficacies and the adverse effects of the analgesic combinations reported in the studies. Drug efficacy was reported by the two objective pain measurements, SPID6 and TOTPAR6 (See Objective pain measurements). Single drug analgesics reported in the included studies were not assessed. The reported SPID6 and TOTPAR6 value of the placebos in the included articles reported and compared with the analgesic combinations. When there were multiple studies reporting the same analgesic combination and same dosage, the mean SPID6 and mean TOTPAR6 of the analgesic combination and the respective placebo was calculated according to the formula:

The adjusted effect of an analgesic combination reported in each included study was calculated by offsetting the placebo effect within the same study to report its actual effect. The formulae to calculate the adjusted SPID6 and TOTPAR6 were as follows:

  1. Adjusted SPID6 = SPID6 of drug—SPID6 of placebo
  2. Adjusted TOTPAR6 = TOTPAR6 of drug—TOTPAR6 of placebo

The adverse effects of the analgesic combinations of the included studies were reported. The proportion of subjects complaining of an adverse effect of the analgesic combination were reported and compared. When there were multiple studies reporting the same analgesic combination of the same dosage, the mean proportion of subjects presenting with the adverse effect were reported.

Objective pain measurements

  1. 1. Sum of pain intensity difference in 6 hours (SPID6). SPID6 measured the difference of the sum of pain intensity score in the first 6 hours post-operatively. Pain intensity score was reported subjectively by the subject on a four-point scale (0 = none; 1 = slight; 2 = moderate; 3 = severe). The baseline pain intensity score was recorded after third molar surgery and local anaesthesic effect was subsided. Analgesics were administered afterwards.

The Pain Intensity Difference (PID) was measured by the pain intensity score at baseline minus the pain intensity score at a given observation time point, which was recorded hourly in the first 6 hours. The sum of Pain Intensity Difference (SPID) for the 0 to 6-hour observation period was reported as SPID6. The higher score represents more effective analgesia.

  1. 2. Total pain relief in 6 hours (TOTPAR6). Pain relief was measured by a categorical rating scale (0 = none; 1 = slight; 2 = moderate; 3 = good; 4 = complete). Pain relief after analgesic consumption was recorded at different post-operative time points, which was recorded hourly in the first 6 hours. The summation of pain relief score on each hour in the first 6 hours resulted in TOTPAR 6. It was defined as the area under the curve of the pain relief scores against the corresponding time interval. For example if a patient had complete pain relief immediately after taken the analgesic, and sustained it for the full 6 hours of observation period, the maximum TOTPAR6 would be (6 hours x 4) 24. The higher the score represented the analgesic was more effective.

Data Synthesis

Meta-analysis of the data was performed by first looking at the heterogeneity of the studies included in this paper. Cochrane Q and quantification of dispersion between studies using I2, values were calculated using Comprehensive Meta-Analysis (version 2.2.064, Englewood, New Jersey). The random effects model was chosen and significance level was set at 0.05.

The manuscript was based on a master thesis of the first author, which was submitted in September 2013 to the University of Hong Kong. The meta-analysis of the study was performed by the second author. A re-search was performed in September 2014 using the keywords and found no new studies to be included. The authors therefore prefer to use the original search date for the systematic review and meta-analysis.

Results

A flow diagram of the three rounds of search and evaluation was presented in Fig 1. The first round search of the computer base, covering the period from the earliest available date to 1st March 2013, yielded 896 hits from PubMed, 137 hits from Medline and 82 hits from the Cochrane Library. One hundred and eighty three hits were duplications and were removed. The abstracts of 932 articles were screened, 365 articles were considered relevant to the study of the efficacy and clinical safety of analgesic combination of post-operative acute dental pain, with 567 articles were considered irrelevant and were excluded. The second round search yielded 4 additional articles from manual search and 4 additional articles from reference search. After selection, 71 articles met the three criteria and entered the third round for evaluation. Fifty-eight studies failed to meet one or more of the criteria in the evaluation round and were excluded. Fourteen studies fulfilled the eligibility criteria and entered the final review.

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Fig 1. Flow diagram for article selection.

https://doi.org/10.1371/journal.pone.0127611.g001

General findings

The 14 included studies [13–25] of the final review were all randomized clinical trial with placebo control. These articles were published between 1986 and 2012. Two were multi-center studies [21, 25], thirteen were double blinded single oral dose studies [13, 14, 16–25] and one study was double blinded with repeated doses [15]. All studies reported the basic demographic data.

There were a total of 3521 subjects included the 14 included studies. Of these, 1748 subjects received different combinations and dosages of analgesics and 629 subjects received placebo. The remaining 1144 subjects of these studies had single drug analgesics and were excluded from the review.

Ten groups of drug combinations were identified in the final review according to the type of drug combined. They were 1) acetaminophen + codeine phosphate; 2) acetaminophen + hydrocodone bitartrate; 3) acetaminophen + oxycodone HCL; 4) acetaminophen + ibuprofen 5) aspirin + caffeine; 6) aspirin + codeine phosphate; 7) aspirin + caffeine + butalbital + codeine phosphate; 8) ibuprofen + oxycodone HCL; and 9) ibuprofen + caffeine; 10) ibuprofen + codeine phosphate

There were 17 drug combinations with different dosages and were listed below.

  1. Acetaminophen 650mg + codeine phosphate 60mg
  2. Acetaminophen 600mg + codeine phosphate 60mg
  3. Acetaminophen 300mg + codeine phosphate 30mg
  4. Acetaminophen 1g + codeine phosphate 30mg
  5. Acetaminophen 1g + hydrocodone bitartrate 10mg
  6. Acetaminophen 500mg + hydrocodone bitartrate 7.5mg
  7. Acetaminophen 325mg + oxycodone HCL 5mg
  8. Acetaminophen 500mg + ibuprofen 200mg
  9. Acetaminophen 1g + ibuprofen 400mg
  10. Aspirin 650mg + caffeine 65mg
  11. Aspirin 650mg + codeine phosphate 60mg
  12. Aspirin 325mg + caffeine 40mg + butalbital 50mg + codeine phosphate 15mg
  13. Ibuprofen 400mg + oxycodone HCL 5mg
  14. Ibuprofen 200mg + caffeine 200mg
  15. Ibuprofen 200mg + caffeine 100mg
  16. Ibuprofen 200mg + caffeine 50mg
  17. Ibuprofen 400mg + codeine phosphate 25.6mg

Efficacy of analgesic combinations

The efficacies of the analgesic combinations in terms of SPID6 and TOTPAR6 were reported in Table 3.

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Table 3. Summary of efficacy of various analgesic combinations of the included studies.

https://doi.org/10.1371/journal.pone.0127611.t003

Seven of the 17 different analgesic combinations with different dosages described in the included studies involved acetaminophen combining with an opioid (codeine phosphate, hydrocodone bitartrate or oxycodone HCL), with the adjusted SPID6 and adjusted TOTPAR6 of ranged from 1.46–3.7 and 3.24–7.2 respectively. Four of these combinations involved different dosages of acetaminophen combined with codeine phosphate. There was no obvious difference of efficacy in terms of SPID6 and TOTPAR6 between acetaminophen 650mg + codeine phosphate 60mg and acetaminophen 600mg + codeine phosphate 60mg. But these two combinations were more effective than acetaminophen 300mg + codeine phosphate 30mg, with adjusted SPID6 and adjusted TOTPAR6 at least 2.1 and 1.6 times higher, respectively, than the lower dosage combination.

Three of the analgesic combinations from the included studies involved aspirin as a major analgesic component, with the adjusted SPID6 and adjusted TOTPAR6 were ranged from 1.8–3.09 and 4.4–6.7, respectively. The four drugs combination of aspirin 325mg+caffeine 40mg + butalbital 50mg + codeine phosphate 15mg showed the highest efficacy in terms of adjusted SPID6 (3.09) and TOTPAR6 (6.7) among the three, followed by aspirin 650mg + caffeine 65mg and aspirin 650mg + codeine phosphate 60mg.

Seven of the analgesic combinations reported in the included studies had ibuprofen as a major analgesic component, with the adjusted SPID6 and adjusted TOTPAR6 were ranged from 1.5–6.44 and 7.0–10.3, respectively. Ibuprofen 400mg + oxycodone HCL 5mg showed the highest adjusted SPID6 then the other three combinations of ibuprofen with caffeine in different dosages, which was at least 1.84 times better in adjusted SPID6. For the analgesic combinations of ibuprofen with caffeine, it seemed that the analgesic efficacy did not drastically increase when the dosage of caffeine was increase from 100mg to 200mg, which was interpreted by similar adjusted SPID6 and TOTPAR6 findings. However, ibuprofen 200mg + caffeine 50mg was obviously less effective when compared to the two combinations of ibuprofen 200mg and caffeine in higher dosages.

Among the 17 different analgesic combinations reported in the included studies, ibuprofen 400mg + oxycodone HCL 5mg had the highest adjusted SPID6 (6.44), and a very higher adjusted TOTPAR6 (9.31), representing its efficacy could be the superior than the other different analgesic combinations reported in this study.

Meta-analysis and Forest plots

Studies were analyzed separately both according to the SPID6, and then according to the TOTPAR6 scores obtained. The observed between study dispersion, (Cochrane Q value) calculated according to SPID6 and TOTPAR were both p<0.0001, with 17 degrees of freedom (18 studies being included in this analysis) which shows homogenous treatment according to the random effects model. The I2 value calculated according to SPID6 and TOTPAR was both 0.0%, which represents less than moderate heterogeneity. Forest plots were presented according to either SPID6, or TOTPAR (Figs 2 and 3). Both figures confirmed all analgesic combinations were better than the placebo, and showed Ibuprofen 400mg with oxycodone 5mg offered the highest analgesic effect after lower third molar surgery.

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Fig 2. Forest plot according to SPID6.

https://doi.org/10.1371/journal.pone.0127611.g002

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Fig 3. Forest plot according to TOTPAR.

https://doi.org/10.1371/journal.pone.0127611.g003

Safety of analgesic combinations

The summary of the adverse effects of the various analgesic combinations from the included studies was listed in Table 4. The common adverse effects were mostly related to the side effects of opioids, including drowsiness, dizziness, headache and nausea. Nausea was the most common adverse effect in opioids containing combinations, ranging from 2.4% to 55%. Other rarer adverse effects (e.g. leg numbness, chills, itchy, dry mouth, sweating) were also reported in most of the analgesic combinations but in general the prevalence was low.

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Table 4. Summary of reported adverse effects of various analgesic combinations of the included studies.

(N.R. = Not Reported).

https://doi.org/10.1371/journal.pone.0127611.t004

Among the 7 combinations of acetaminophen and an opioids (codeine phosphate, hydrocodone bitartrate or oxycodone HCL), it was noted acetaminophen 1g + hydrocodone bitartrate 10mg had the highest incidence of adverse effects, with 55% of the subjects complaining of nausea or vomiting, 22.4% of the subjects with dizziness, 15% with headache and 10.5% with drowsiness. Acetaminophen 500mg + hydrocodone bitartrate 7.5mg was reported to have fewer subjects with adverse effect, which was likely to be related to the reduced dosage of hydrocodone bitartrate, with only 15.25% of the subjects experienced nausea and 8.47% with drowsiness. There were also 41% of the subjects who took the combination of acetaminophen 325mg and oxycodone HCL 5mg experienced nausea. The combinations of acetaminophen and codeine phosphate had fewer adverse effects reported when compared to the combinations of acetaminophen and hydrocodone bitartrate or oxycodone HCL. From the included studies, it seemed that reduced dosages of acetaminophen and codeine phosphate did not result in a reduced incidence of the side effects of the opioids.

The adverse effects of the two studies reported the use of ibuprofen 400mg + oxycodone HCL 5mg were pooled. The prevalence of the subjects who experienced drowsiness was 13.25%. The other adverse effects were related to the side effect of the opioid oxycodone HCL but the prevalences were low (0.4–2.4%).

In contrast to the analgesic combinations containing opioids, combinations of an NSAID with caffeine were reported to have much fewer adverse effects. In the same study reporting combinations of ibuprofen 200mg and 3 different dosages of caffeine, there seemed to have no obvious difference in terms of prevalence of adverse effect with the increased dosage (up to caffeine 200mg).

Discussion

Systematic reviews and meta-analyses have become increasingly popular in medicine [26, 27]. It helps clinicians to keep up-to-date clinical practice guideline and facilitate researchers to use them as a starting point for new guideline formation and future research [28, 29]. It can also provide a high-level overview of a particular research or clinical question by the process of identify, select, synthesize and appraise all high quality research evidence [30]. According to the oxford levels of evidence, systematic review of randomized controlled trials (RCT) is considerate to be level 1 evidence [27]. This study tried to summarize objectively the efficacy and clinical safety of various analgesic combination of post-operative acute dental pain. There were only randomized controlled trials (RCT) with placebo were selected into the final round for analysis, the protocol was straightly followed the PRISMA statement (Preferred Reporting Items for Systematic reviews and Meta-Analyses) [31] and it helps to ensure the clarity and transparency of the systematic reviews conducted.

Post-operative pain after third molar surgery has become a frequently used model in the studies of acute pain clinical trials. This is because third molar surgery is one of the commonest procedure with sufficient numbers of patients to make studies relatively easy to perform [32]. It is also a sensitive method for demonstrating the efficacy of oral analgesic agents [19]. It is because the patient sample in dental pain model is homogenous in pain stimulus, and the post-operative pain is frequently moderate or severe in intensity. Moreover, absence of multiple surgical complication factors comparing to other major surgical procedures, trauma, or other pain stimuli reduced to variables of the surgical procedure and outcome. In addition, third molar surgical procedures can be easily categorized, and the obtained data in dental pain model can substantiate the assay sensitivity of the clinical trials, and therefore it is useful in predicting the general analgesic efficacy of NSAIDs [33, 34].

Pooling of data in a systematic review were occasionally criticized to be “mixing apples and oranges”, especially if there were obvious heterogeneity of the included studies. In this study, the heterogeneity of the included studies in the Final Review has been tested to be less than moderate (I2 = 0.0%), which enabled a representable meta-analysis to be performed.

The measurement of analgesic efficacy is usually performed by comparing patient’s subjective evaluation of pain before and after administration of the analgesics [35]. For a long time, SPID and TOTPAR are the most commonly used methods to measure the efficacy of an analgesic and were well validated [36–38]. They were used in the research context for comparisons between the efficacies of different analgesics [39], and now routinely used in analgesic studies [40–42]. In this systematic review, formulae of adjusted SPID and adjusted TOTPAR were developed by correction of the placebo effect of the respective studies of the analgesics. This may allow direct cross-studies comparison of the analgesic combination efficacies and to reduce the heterogeneity of the placebo effects in different studies.

Analgesic combinations have been proved to be more effective in pain control when compared to single drug [43, 44]. The concurrent use of ibuprofen and paracetamol was the most widely studied analgesic combination. It was shown in a Cochrane Review that 400mg ibuprofen / 1000mg paracetamol combination has superior analgesic effect when compared to ibuprofen or paracetamol alone or the combination of the two of lower dosage [44]. However, there were no other meta-analysis in the literature comparing the effectiveness and side effects of different analgesic combinations.

This systematic review and meta-analysis of analgesic combinations reported the objective analgesic efficacy and the adverse effects of various analgesic combinations studied in the literature. One of the key findings of this study was ibuprofen 400mg + oxycodone HCL 5mg was found to have the most effective analgesic effects in acute dental pain as measured by the objective efficacy measurements of SPID6 and TOTPAR6. It was reported in the literature that ibuprofen 400mg have a stronger analgesic efficacy than acetaminophen 1g [45, 46]. Post-operative inflammation may magnify the process of acute pain signals which potentially lead to greater pain nociception [47–50]. The anti-inflammatory action may therefore provide a higher analgesic efficacy. Moreover, oxycodone HCL is a stronger opioid when compared to codeine phosphate and hydrocodone bitartrate. According the equianalgesia chart [51, 52], the analgesic potency of oxycodone HCL is around 1.5–2.0 times stronger than hydrocodone bitartrate and 15–20 times stronger than codeine phosphate. The combination of the two analgesics therefore was found to be superior in terms of analgesic efficacy when compared to the other combinations.

Acetaminophen and codeine phosphate combination is a common analgesic combination in clinical practice. Acetaminophen mechanism of action is not fully understood [3]. It was suggested that the mechanism of acetaminophen may be related to inhibition of the nitric oxide synthase [51], reduction of spinal prostaglandin E2 release [53], or reversal of the hyperalgesia induced by N-methyl-D-aspartate (NMDA) [54, 55]. The side-effects of acetaminophen are minimal. Unlike NSAIDs, acetaminophen is not likely to cause gastrointestinal irritation. The prevalence of allergic reaction to acetaminophen is rarer when compared to the NSAIDs counterpart. We noted the efficacy of acetaminophen 600mg + codeine phosphate 60mg was doubled when compared to acetaminophen 300mg + codeine phosphate 30mg. We therefore concluded for post-operative pain control after third molar surgery, a higher dosage of acetaminophen and codeine phosphate combination would be better in terms of analgesic efficacy. However, it was also noted the raised dosage of codeine phosphate was related to an elevated prevalence of drowsiness, which might not favorable especially to drivers or machine operators. Taking all these factors into considerations, we recommend the combination of acetaminophen 600mg and codeine phosphate 60mg is effective for post-operative pain after third molar surgery, and may be useful when the patient is allergic to NSAIDs.

We noted most of the adverse effects of the combined analgesics from the included studies were mostly contributed by centrally acting analgesic i.e. codeine phosphate, hydrocodone bitartrate or oxycodone HCL. Their common side effects include drowsiness, dizziness, headache and nausea and vomiting [56, 57]. Other possible adverse effects of opioids described in literature e.g. itching, dry mouth, flashes, sweating and chills were also reported in our study but in a low prevalence [3, 58]. Severe adverse reactions of opioids in patients including tolerance, dependence, confusion, hallucinations, delirium, hypothermia, bradycardia/tachycardia, orthostatic hypotension and urinary retention were not found in our study [56, 57]. We believed those uncommon adverse effects were more likely found in prolonged use of opioids in chronic pain patients [59–61]. It was therefore very unlikely that a short-course use of analgesic for acute dental post-operative pain would lead to these major adverse effects or severe complications. Clinicians have an important role to prescribe appropriate dosing such that patients could gain the analgesic effects with the least adverse effects. Under suitable dosage, central acting analgesic could be an effective and safe medication for the treatment of acute dental post-operative pain.

One of the randomized clinical trials included in the final review compared 3 different dosages of the combination of ibuprofen and caffeine. Caffeine is the central-nervous-system stimulant which is an antagonist of adenosine receptors in the brain [62]. High dose of caffeine may cause tolerance, insomnia, hallucination, reduced control of fine motor movements [52, 63–65]. We reported the adverse effects of the combinations of ibuprofen and caffeine was minimal when compared to other combinations containing opioids. We also found the analgesic efficacies of ibuprofen 200mg with caffeine 100mg or 200mg were similar, with both much superior than with caffeine 50mg. We presumed that the caffeine ceiling dose may be approximately at around 100mg and the combination of ibuprofen 200mg with caffeine 200mg might not have an extra benefit in its analgesic effect.

The limitations of this systematic review and meta-analysis included the possibilities of reporting bias. Some pharmacological studies were sponsored by pharmaceutical companies, which might only report favourable outcomes if a drug combination was shown to be superior. Furthermore, our group did not request centers and companies to report if they had unpublished data on this topic, which might not find all related studies or data about the clinical question we defined.

In this study, the commonly reported adverse effects of NSAIDs (e.g. dyspepsia, gastric ulceration/bleeding, diarrhea) were not found in the drug combinations. Non-selective NSAIDs inhibit both cyclooxygenases (COX): COX-1 and COX-2 which reduce the levels of protective prostaglandins, leading to increase in gastric acid secretion and diminish bicarbonate secretion and mucus secretion [66, 67]. The included studies reported the use of analgesic combinations containing NSAIDs only in a very short course for the acute dental pain. The dosages and the duration of taking NSAIDs might not be sufficient to induce an obvious adverse effect in most patients. The introduction of COX-2 selective inhibitors was reported to have a strong analgesic effect with less adverse effect on the gastrointestinal tract when compared to the non-selective NSAIDs. Stichtenoth DO and Frölich JC have suggested that selective COX-2 inhibitors have significantly less gastric events and no effects on platelet aggregation [68]. However, a COX 2 selective inhibitor was found to increase cardiovascular risks and was withdrawn from the market [69, 70]. There are several COX-2 selective inhibitors still in the market and are found to be safe to use. In this study, there was no well conducted RCT on the efficacy and safety of analgesic combinations with a COX-2 selective inhibitor included in the final review. We therefore recommend future research to investigate the efficacy and side effects on the combination of COX-2 to another group of analgesic, which may potentially be a good analgesic choice for post-operative pain after third molar surgery.

Conclusion

This systematic review and meta-analysis of randomized clinical trials has presented the efficacy and adverse effects of the various analgesic combinations for acute post-operative dental pain control. We have identified ibuprofen 400mg with oxycodone 5mg was more effective when compared to the other 16 combinations. Nausea was the most common adverse effects in an analgesic combination containing an opioid. Ibuprofen 200mg with caffeine 100mg or 200mg has a reasonable analgesic effect with fewer side effects when compared to the other analgesic combinations.

Author Contributions

Conceived and designed the experiments: AHYA YYL. Performed the experiments: AHYA YYL. Analyzed the data: AHYA SWC CWC YYL. Contributed reagents/materials/analysis tools: AHYA LYY. Wrote the paper: AHYA SWC CWC YYL.

References

  1. 1. A M, I P. Perioperative NSAIDs: towards greater safety. Pain Rev. 1995;2:268–91.
  2. 2. Romsing J, Moiniche S, Dahl JB. Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia. British journal of anaesthesia. 2002;88(2):215–26. Epub 2002/03/07. pmid:11878655.
  3. 3. Raffa RB. Pharmacology of oral combination analgesics: rational therapy of pain. Journal of Clinical Pharmacy and Therapeutics. 2001;26:257–64. pmid:11493367
  4. 4. Besson JM. The neurobiology of pain. Lancet. 1999;353(9164):1610–5. Epub 1999/05/20. pmid:10334274.
  5. 5. Schug SA, Zech D, Dorr U. Cancer pain management according to WHO analgesic guidelines. Journal of pain and symptom management. 1990;5(1):27–32. Epub 1990/02/01. pmid:2324558.
  6. 6. I G. Principles of Analgesic Use in the Treatment of Acute pain and Cancer pain: American Pain Society.; 1999.
    • 7. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis and rheumatism. 2000;43(9):1905–15. Epub 2000/10/03. pmid:11014340.
    • 8. Cheung CW, Choi WS, Leung YY, Lui F, Ng JK, Hei-Ho AM, et al. A double-blind randomized crossover study to evaluate the timing of pregabalin for third molar surgery under local anesthesia. Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons. 2012;70(1):25–30. Epub 2011/08/09. pmid:21820233.
    • 9. Qi DS, May LG, Zimmerman B, Peng P, Atillasoy E, Brown JD, et al. A randomized, double-blind, placebo-controlled study of acetaminophen 1000 mg versus acetaminophen 650 mg for the treatment of postsurgical dental pain. Clinical therapeutics. 2012;34(12):2247–58.e3. Epub 2012/12/04. pmid:23200183.
    • 10. Hassan SS, Ahmed A, Rai M, Kalappa TM. Analgesic efficacy of tramadol and butorphanol in mandibular third molar surgery: a comparative study. The journal of contemporary dental practice. 2012;13(3):364–70. Epub 2012/08/25. pmid:22918011.
    • 11. Moll R, Derry S, Moore RA, McQuay HJ. Single dose oral mefenamic acid for acute postoperative pain in adults. The Cochrane database of systematic reviews. 2011;(3):Cd007553. Epub 2011/03/18. pmid:21412904; PubMed Central PMCID: PMCPmc4170999.
    • 12. Curatolo M, Sveticic G. Drug combinations in pain treatment: a review of the published evidence and a method for finding the optimal combination. Best practice & research Clinical anaesthesiology. 2002;16(4):507–19. Epub 2003/01/09. pmid:12516888.
    • 13. Cooper SA, Firestein A, Cohn P. Double-blind comparison of meclofenamate sodium with acetaminophen, acetaminophen with codeine and placebo for relief of postsurgical dental pain. The Journal of clinical dentistry. 1988;1(2):31–4. Epub 1988/01/01. pmid:3254707.
    • 14. Forbes JA, Bates JA, Edquist IA, Burchfield WH, Smith FG, Schwartz MK, et al. Evaluation of two opioid-acetaminophen combinations and placebo in postoperative oral surgery pain. Pharmacotherapy. 1994;14(2):139–46. Epub 1994/03/01. pmid:8197031.
    • 15. Forbes JA, Butterworth GA, Burchfield WH, Beaver WT. Evaluation of ketorolac, aspirin, and an acetaminophen-codeine combination in postoperative oral surgery pain. Pharmacotherapy. 1990;10(6 (Pt 2)):77s–93s. Epub 1990/01/01. pmid:2082317.
    • 16. Forbes JA, Butterworth GA, Burchfield WH, Yorio CC, Selinger LR, Rosenmertz SK, et al. Evaluation of flurbiprofen, acetaminophen, an acetaminophen-codeine combination, and placebo in postoperative oral surgery pain. Pharmacotherapy. 1989;9(5):322–30. Epub 1989/01/01. pmid:2813153.
    • 17. Forbes JA, Jones KF, Kehm CJ, Smith WK, Gongloff CM, Zeleznock JR, et al. Evaluation of Aspirin, Caffeine, and Their Combination in Postoperative Oral Surgery Pain. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 1990;10(6):387–94.
    • 18. Forbes JA, Jones KF, Smith WK, Gongloff CM. Analgesic effect of an aspirin-codeine-butalbital-caffeine combination and an acetaminophen-codeine combination in postoperative oral surgery pain. Pharmacotherapy. 1986;6(5):240–7. Epub 1986/09/01. pmid:3540875.
    • 19. Fricke J, Halladay SC, Bynum L, Francisco CA. Pain relief after dental impaction surgery using ketorolac, hydrocodone plus acetaminophen, or placebo. Clinical therapeutics. 1993;15(3):500–9. Epub 1993/05/01. pmid:8364942.
    • 20. Gatoulis SC, Voelker M, Fisher M. Assessment of the efficacy and safety profiles of aspirin and acetaminophen with codeine: results from 2 randomized, controlled trials in individuals with tension-type headache and postoperative dental pain. Clinical therapeutics. 2012;34(1):138–48. Epub 2011/12/16. pmid:22169050.
    • 21. Litkowski LJ, Christensen SE, Adamson DN, Van Dyke T, Han SH, Newman KB. Analgesic efficacy and tolerability of oxycodone 5 mg/ibuprofen 400 mg compared with those of oxycodone 5 mg/acetaminophen 325 mg and hydrocodone 7.5 mg/acetaminophen 500 mg in patients with moderate to severe postoperative pain: a randomized, double-blind, placebo-controlled, single-dose, parallel-group study in a dental pain model. Clinical therapeutics. 2005;27(4):418–29. Epub 2005/06/01. pmid:15922815.
    • 22. McQuay HJ, Angell K, Carroll D, Moore RA, Juniper RP. Ibuprofen compared with ibuprofen plus caffeine after third molar surgery. Pain. 1996;66(2–3):247–51. Epub 1996/08/01. pmid:8880847.
    • 23. Moore PA, Crout RJ, Jackson DL, Schneider LG, Graves RW, Bakos L. Tramadol hydrochloride: analgesic efficacy compared with codeine, aspirin with codeine, and placebo after dental extraction. Journal of clinical pharmacology. 1998;38(6):554–60. Epub 1998/07/03. pmid:9650546.
    • 24. Sunshine A, Marrero I, Olson N, McCormick N, Laska EM. Comparative study of flurbiprofen, zomepirac sodium, acetaminophen plus codeine, and acetaminophen for the relief of postsurgical dental pain. The American journal of medicine. 1986;80(3a):50–4. Epub 1986/03/24. pmid:3515924.
    • 25. Van Dyke T, Litkowski LJ, Kiersch TA, Zarringhalam NM, Zheng H, Newman K. Combination oxycodone 5 mg/ibuprofen 400 mg for the treatment of postoperative pain: a double-blind, placebo- and active-controlled parallel-group study. Clinical therapeutics. 2004;26(12):2003–14. Epub 2005/04/13. pmid:15823764.
    • 26. Moher D, Tetzlaff J, Tricco AC, Sampson M, Altman DG. Epidemiology and reporting characteristics of systematic reviews. PLoS medicine. 2007;4(3):e78. Epub 2007/03/29. pmid:17388659; PubMed Central PMCID: PMCPmc1831728.
    • 27. Medicine OCfE-B. 2011. Available from: http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/.
      • 28. Young C, Horton R. Putting clinical trials into context. Lancet. 2005;366(9480):107–8. Epub 2005/07/12. pmid:16005318.
      • 29. Stevens A, Shamseer L, Weinstein E, Yazdi F, Turner L, Thielman J, et al. Relation of completeness of reporting of health research to journals' endorsement of reporting guidelines: systematic review. BMJ (Clinical research ed). 2014;348:g3804. Epub 2014/06/27. pmid:24965222; PubMed Central PMCID: PMCPmc4070413.
      • 30. Library C. About Cochrane Systematic Reviews. Available from: http://www.thecochranelibrary.com/view/0/AboutCochraneSystematicReviews.html.
        • 31. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10):e1–34. Epub 2009/07/28. pmid:19631507.
        • 32. Barden J, Edwards JE, McQuay HJ, Andrew Moore R. Pain and analgesic response after third molar extraction and other postsurgical pain. Pain. 2004;107(1–2):86–90. Epub 2004/01/13. pmid:14715393.
        • 33. Cooper SA. Models for clinical assessment of oral analgesics. The American journal of medicine. 1983;75(5a):24–9. Epub 1983/11/14. pmid:6359864.
        • 34. Cooper SA, Beaver WT. A model to evaluate mild analgesics in oral surgery outpatients. Clinical pharmacology and therapeutics. 1976;20(2):241–50. Epub 1976/08/01. pmid:780041.
        • 35. McMahon S, Koltzenburg M, Tracey I. Wall DC & Melzack's Textbook of Pain.
          • 36. Laska EM, Meisner M, Takeuchi K, Wanderling JA, Siegel C, Sunshine A. An analytic approach to quantifying pain scores. Pharmacotherapy. 1986;6(5):276–82. Epub 1986/09/01. pmid:3797261.
          • 37. Bloomfield SS, Mitchell J, Cissell G, Barden TP. Analgesic sensitivity of two post-partum pain models. Pain. 1986;27(2):171–9. Epub 1986/11/01. pmid:3540812.
          • 38. Sriwatanakul K, Lasagna L, Cox C. Evaluation of current clinical trial methodology in analgesimetry based on experts' opinions and analysis of several analgesic studies. Clinical pharmacology and therapeutics. 1983;34(3):277–83. Epub 1983/09/01. pmid:6883903.
          • 39. CR B, JY T. Statistics in the Pharmaceutical Industry. 3rd Edition ed: Raton: Chapman & Hall/CRC; 2006.
            • 40. Barden J, Edwards J, Moore RA, McQuay HJ. Single dose oral rofecoxib for postoperative pain. The Cochrane database of systematic reviews. 2005;(1):Cd004604. Epub 2005/01/28. pmid:15674955.
            • 41. Traa MX, Derry S, Moore RA. Single dose oral fenoprofen for acute postoperative pain in adults. The Cochrane database of systematic reviews. 2011;(2):Cd007556. Epub 2011/02/18. pmid:21328296; PubMed Central PMCID: PMCPmc4171001.
            • 42. Derry S, Moore RA. Single dose oral celecoxib for acute postoperative pain in adults. The Cochrane database of systematic reviews. 2012;3:Cd004233. Epub 2012/03/16. pmid:22419293; PubMed Central PMCID: PMCPmc4161494.
            • 43. Moore RA, Straube S, Paine J, Derry S, McQuay HJ. Minimum efficacy criteria for comparisons between treatments using individual patient meta-analysis of acute pain trials: examples of etoricoxib, paracetamol, ibuprofen, and ibuprofen/paracetamol combinations after third molar extraction. Pain. 2011;152(5):982–9. Epub 2011/03/19. pmid:21414722.
            • 44. Bailey E, Worthington H, Coulthard P. Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth, a Cochrane systematic review. British dental journal. 2014;216(8):451–5. Epub 2014/04/26. pmid:24762895.
            • 45. Cooper SA. Five studies on ibuprofen for postsurgical dental pain. The American journal of medicine. 1984;77(1a):70–7. Epub 1984/07/13. pmid:6465164.
            • 46. Hersh EV, Levin LM, Cooper SA, Doyle G, Waksman J, Wedell D, et al. Ibuprofen liquigel for oral surgery pain. Clinical therapeutics. 2000;22(11):1306–18. Epub 2000/12/16. pmid:11117655.
            • 47. Barkin RL. Acetaminophen, aspirin, or Ibuprofen in combination analgesic products. American journal of therapeutics. 2001;8(6):433–42. Epub 2001/11/13. pmid:11704782.
            • 48. Davies J, McVicar A. Issues in effective pain control. 2: From assessment to management. International journal of palliative nursing. 2000;6(4):162–9. Epub 2001/01/06. pmid:11143642.
            • 49. Cross SA. Pathophysiology of pain. Mayo Clinic proceedings. 1994;69(4):375–83. Epub 1994/04/01. pmid:8170183.
            • 50. Charts E. Available from: http://www3.us.elsevierhealth.com/pain/pdf/Chart1a.pdf
              • 51. Multidisciplinary Pain Center UoAOcG. Available from: Http://www.uofapain.med.ualberta.ca/.
                • 52. BjoÈrkman R HK, Hedner J, Hedner T,Henning M. Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P. Pain. 1994;57:259–64. pmid:7524008
                • 53. Muth-Selbach US, Tegeder I, Brune K, Geisslinger G. Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation. Anesthesiology. 1999;91(1):231–9. Epub 1999/07/28. pmid:10422949.
                • 54. Hunskaar S, Fasmer OB, Hole K. Acetylsalicylic acid, paracetamol and morphine inhibit behavioral responses to intrathecally administered substance P or capsaicin. Life sciences. 1985;37(19):1835–41. Epub 1985/11/11. pmid:2414631.
                • 55. Bjorkman R. Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Experimental studies in the rat. Acta anaesthesiologica Scandinavica Supplementum. 1995;103:1–44. Epub 1995/01/01. pmid:7725891.
                • 56. Carr D, Eisenburg E, Fricton J, Giamberardino M, Goh C, A J. Pain updates opioid side effects. Int Assoc Study Pain: 2007.
                • 57. Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, et al. Opioid complications and side effects. Pain physician. 2008;11(2 Suppl):S105–20. Epub 2008/06/17. pmid:18443635.
                • 58. Laska EM, Sunshine A, Marrero I, Olson N, Siegel C, McCormick N. The correlation between blood levels of ibuprofen and clinical analgesic response. Clinical pharmacology and therapeutics. 1986;40(1):1–7. Epub 1986/07/01. pmid:3522030.
                • 59. Portenoy RK. Opioid therapy for chronic nonmalignant pain: a review of the critical issues. Journal of pain and symptom management. 1996;11(4):203–17. Epub 1996/04/01. pmid:8869456.
                • 60. Ballantyne JC, Mao J. Opioid therapy for chronic pain. The New England journal of medicine. 2003;349(20):1943–53. Epub 2003/11/14. pmid:14614170.
                • 61. Nehlig A, Daval JL, Debry G. Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain research Brain research reviews. 1992;17(2):139–70. Epub 1992/05/01. pmid:1356551.
                • 62. Smith A. Effects of caffeine on human behavior. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association. 2002;40(9):1243–55. Epub 2002/09/03. pmid:12204388.
                • 63. Cornelis MC, El-Sohemy A. Coffee, caffeine, and coronary heart disease. Current opinion in clinical nutrition and metabolic care. 2007;10(6):745–51. Epub 2007/12/20. pmid:18089957.
                • 64. Lovallo WR, Whitsett TL, al'Absi M, Sung BH, Vincent AS, Wilson MF. Caffeine stimulation of cortisol secretion across the waking hours in relation to caffeine intake levels. Psychosomatic medicine. 2005;67(5):734–9. Epub 2005/10/06. pmid:16204431; PubMed Central PMCID: PMCPmc2257922.
                • 65. Crowe SF, Barot J, Caldow S, D’Aspromonte J, Dell’Orso J, Di Clemente A, et al. The effect of caffeine and stress on auditory hallucinations in a non-clinical sample. Personality and Individual Differences. 2011;50(5):626–30.
                • 66. Venkat K, Brown MD, Barkin R. Nonsteroidal anti-inflammatory drugs and gastroduodenal injury. American journal of therapeutics. 1998;5(4):263–72. Epub 1999/03/31. pmid:10099068.
                • 67. Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115(12):1634–42. Epub 2007/02/28. pmid:17325246.
                • 68. Stichtenoth DO, Frolich JC. The second generation of COX-2 inhibitors: what advantages do the newest offer? Drugs. 2003;63(1):33–45. Epub 2002/12/19. pmid:12487621.
                • 69. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ (Clinical research ed). 2006;332(7553):1302–8. Epub 2006/06/03. pmid:16740558; PubMed Central PMCID: PMCPmc1473048.
                • 70. Cannon CP, Cannon PJ. Physiology. COX-2 inhibitors and cardiovascular risk. Science (New York, NY). 2012;336(6087):1386–7. Epub 2012/06/16. pmid:22700906.
                • 71. Sveen K, Gilhuus-Moe O. Paracetamol/codeine in relieving pain following removal of impacted mandibular third molars. International journal of oral surgery. 1975;4(6):258–66. Epub 1975/12/01. pmid:815188.
                • 72. Hellem S, Persson G, Freiberg N, Nord PG, Gustafsson B, Huitfeldt B. A model for evaluating the analgesic effect of a new fixed ratio combination analgesic in patients undergoing oral surgery. International journal of oral surgery. 1979;8(6):435–42. Epub 1979/12/01. pmid:120341.
                • 73. Forbes JA, Bowser MW, Calderazzo JP, Foor VM. An evaluation of the analgesic efficacy of three opioid-analgesic combinations in postoperative oral surgery pain. Journal of oral surgery (American Dental Association: 1965). 1981;39(2):108–12. Epub 1981/02/01. pmid:6936524.
                • 74. Quiding H, Oikarinen V, Huitfeldt B, Koskimo M, Leikomaa H, Nyman C. An analgesic study with repeated doses of phenazone, phenazone plus dextropropoxyphene, and paracetamol, using a visual analogue scale. International journal of oral surgery. 1982;11(5):304–9. Epub 1982/10/01. pmid:6818169.
                • 75. Quiding H, Persson G, Ahlstrom U, Bangens S, Hellem S, Johansson G, et al. Paracetamol plus supplementary doses of codeine. An analgesic study of repeated doses. European journal of clinical pharmacology. 1982;23(4):315–9. Epub 1982/10/01. pmid:6756936.
                • 76. Edmondson HD, Bradshaw AJ. Analgesia following oral surgery: a comparative study of Solpadeine and a soluble form of dextropropoxyphene napsylate and paracetamol. The Journal of international medical research. 1983;11(4):228–31. Epub 1983/01/01. pmid:6137427.
                • 77. Laska EM, Sunshine A, Zighelboim I, Roure C, Marrero I, Wanderling J, et al. Effect of caffeine on acetaminophen analgesia. Clinical pharmacology and therapeutics. 1983;33(4):498–509. Epub 1983/04/01. pmid:6831829.
                • 78. Dionne RA, Wirdezk PR, Butler DP, Fox PC. Comparison of conorphone, a mixed agonist-antagonist analgesic, to codeine for postoperative dental pain. Anesthesia progress. 1984;31(2):77–81. Epub 1984/03/01. pmid:6597688; PubMed Central PMCID: PMCPmc2515536.
                • 79. Ahlstrom U, Fahraeus J, Quiding H, Strom C. Multiple doses of paracetamol plus codeine taken immediately after oral surgery. European journal of clinical pharmacology. 1985;27(6):693–6. Epub 1985/01/01. pmid:3886395.
                • 80. Dahl E, Feldmann G, Jonsson E. Acetylsalicylic acid compared with acetylsalicylic acid plus codeine as postoperative analgesics after removal of impacted mandibular third molars. Swedish dental journal. 1985;9(5):207–12. Epub 1985/01/01. pmid:3909471.
                • 81. Rosen M, Absi EG, Webster JA. Suprofen compared to dextropropoxyphene hydrochloride and paracetamol (Cosalgesic) after extraction of wisdom teeth under general anaesthesia. Anaesthesia. 1985;40(7):639–41. Epub 1985/07/01. pmid:3896016.
                • 82. Frame JW, Fisher SE, Pickvance NJ, Skene AM. A double-blind placebo-controlled comparison of three ibuprofen/codeine combinations and aspirin. The British journal of oral & maxillofacial surgery. 1986;24(2):122–9. Epub 1986/04/01. pmid:2941056.
                • 83. Happonen RP, Oksala E, Ylipaavalniemi P. A combination of acetylsalicylic acid and codeine phosphate versus acetylsalicylic acid as postoperative analgesics after mandibular third molar surgery. Proceedings of the Finnish Dental Society Suomen Hammaslaakariseuran toimituksia. 1987;83(1):32–5. Epub 1987/01/01. pmid:3562451.
                • 84. Hill CM, Carroll MJ, Giles AD, Pickvance N. Ibuprofen given pre- and post-operatively for the relief of pain. International journal of oral and maxillofacial surgery. 1987;16(4):420–4. Epub 1987/08/01. pmid:3117914.
                • 85. Liashek P Jr., Desjardins PJ, Triplett RG. Effect of pretreatment with acetaminophen-propoxyphene for oral surgery pain. Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons. 1987;45(2):99–103. Epub 1987/02/01. pmid:3468226.
                • 86. Sagne S, Henrikson PA, Kahnberg KE, Thilander H, Bertilson SO. Analgesic efficacy and side-effect profile of paracetamol/codeine and paracetamol/dextropropoxyphene after surgical removal of a lower wisdom tooth. The Journal of international medical research. 1987;15(2):83–8. Epub 1987/03/01. pmid:3556263.
                • 87. Dupuis R, Lemay H, Bushnell MC, Duncan GH. Preoperative flurbiprofen in oral surgery: a method of choice in controlling postoperative pain. Pharmacotherapy. 1988;8(3):193–200. Epub 1988/01/01. pmid:3050905.
                • 88. McQuay HJ, Carroll D, Watts PG, Juniper RP, Moore RA. Codeine 20 mg increases pain relief from ibuprofen 400 mg after third molar surgery. A repeat-dosing comparison of ibuprofen and an ibuprofen-codeine combination. Pain. 1989;37(1):7–13. Epub 1989/04/01. pmid:2726279.
                • 89. Becker J, Beckmann J, Bertelt C, Gundert-Remy U, Rohmel J, Ohlendorf D. [Double blind biometric study on postoperative effects of analgesics]. Deutsche zahnarztliche Zeitschrift. 1990;45(1):36–8. Epub 1990/01/01. pmid:2257800.
                • 90. Giglio JA, Laskin DM. Double-blind comparison of meclofenamate sodium plus codeine, meclofenamate sodium, codeine, and placebo for relief of pain following surgical removal of third molars. Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons. 1990;48(8):785–90. Epub 1990/08/01. pmid:2197381.
                • 91. Habib S, Matthews RW, Scully C, Levers BG, Shepherd JP. A study of the comparative efficacy of four common analgesics in the control of postsurgical dental pain. Oral surgery, oral medicine, and oral pathology. 1990;70(5):559–63. Epub 1990/11/01. pmid:2234874.
                • 92. Walton GM, Rood JP. A comparison of ibuprofen and ibuprofen-codeine combination in the relief of post-operative oral surgery pain. British dental journal. 1990;169(8):245–7. Epub 1990/10/20. pmid:2245092.
                • 93. Skoglund LA, Skjelbred P, Fyllingen G. Analgesic efficacy of acetaminophen 1000 mg, acetaminophen 2000 mg, and the combination of acetaminophen 1000 mg and codeine phosphate 60 mg versus placebo in acute postoperative pain. Pharmacotherapy. 1991;11(5):364–9. Epub 1991/01/01. pmid:1745622.
                • 94. Hellman M, Ahlstrom U, Andersson L, Strid S. Analgesic efficacy of an ibuprofen-codeine combination in patients with pain after removal of lower third molars. European journal of clinical pharmacology. 1992;43(4):347–50. Epub 1992/01/01. pmid:1451712.
                • 95. Lownie JF, Lownie MA, Reinach SG. Comparison of the safety and efficacy of a combination analgesic Myprodol and Ponstan in the treatment of dental pain. The Journal of the Dental Association of South Africa = Die Tydskrif van die Tandheelkundige Vereniging van Suid-Afrika. 1992;47(9):403–6. Epub 1992/09/01. pmid:9511622.
                • 96. Lysell L, Anzen B. Pain control after third molar surgery--a comparative study of ibuprofen (Ibumetin) and a paracetamol/codeine combination (Citodon). Swedish dental journal. 1992;16(4):151–60. Epub 1992/01/01. pmid:1455326.
                • 97. McQuay HJ, Carroll D, Guest P, Juniper RP, Moore RA. A multiple dose comparison of combinations of ibuprofen and codeine and paracetamol, codeine and caffeine after third molar surgery. Anaesthesia. 1992;47(8):672–7. Epub 1992/08/01. pmid:1519716.
                • 98. Dolci G, Ripari M, Pacifici L, Umile A. [Analgesic efficacy and the tolerance for piroxicam-beta-cyclodextrin compared to piroxicam, paracetamol and placebo in the treatment of postextraction dental pain]. Minerva stomatologica. 1993;42(5):235–41. Epub 1993/05/01. pmid:8413108.
                • 99. Petersen JK, Hansson F, Strid S. The effect of an ibuprofen-codeine combination for the treatment of patients with pain after removal of lower third molars. Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons. 1993;51(6):637–40. Epub 1993/06/01. pmid:8492200.
                • 100. Dionne RA, Snyder J, Hargreaves KM. Analgesic efficacy of flurbiprofen in comparison with acetaminophen, acetaminophen plus codeine, and placebo after impacted third molar removal. Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons. 1994;52(9):919–24; discussion 25–6. Epub 1994/09/01. pmid:8064454.
                • 101. Berge TI. Pattern of self-administered paracetamol and codeine analgesic consumption after mandibular third-molar surgery. Acta odontologica Scandinavica. 1997;55(5):270–6. Epub 1997/11/25. pmid:9370023.
                • 102. McGurk M, Robinson P, Rajayogeswaran V, De Luca M, Casini A, Artigas R, et al. Clinical comparison of dexketoprofen trometamol, ketoprofen, and placebo in postoperative dental pain. Journal of clinical pharmacology. 1998;38(12 Suppl):46s–54s. Epub 1999/01/09. pmid:9882082.
                • 103. 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. British journal of anaesthesia. 1998;81(6):875–80. Epub 1999/04/22. pmid:10211012.
                • 104. Breivik EK, Barkvoll P, Skovlund E. Combining diclofenac with acetaminophen or acetaminophen-codeine after oral surgery: a randomized, double-blind single-dose study. Clinical pharmacology and therapeutics. 1999;66(6):625–35. Epub 1999/12/29. pmid:10613619.
                • 105. Dionne RA. Additive analgesic effects of oxycodone and ibuprofen in the oral surgery model. Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons. 1999;57(6):673–8. Epub 1999/06/15. pmid:10368091.
                • 106. Caruso FS. MorphiDex pharmacokinetic studies and single-dose analgesic efficacy studies in patients with postoperative pain. Journal of pain and symptom management. 2000;19(1 Suppl):S31–6. Epub 2000/02/25. pmid:10687337.
                • 107. Ziccardi VB, Desjardins PJ, Daly-DeJoy E, Seng GF. Single-dose vicoprofen compared with acetaminophen with codeine and placebo in patients with acute postoperative pain after third molar extractions. Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons. 2000;58(6):622–8. Epub 2000/06/10. pmid:10847283.
                • 108. Medve RA, Wang J, Karim R. Tramadol and acetaminophen tablets for dental pain. Anesthesia progress. 2001;48(3):79–81. Epub 2001/11/29. pmid:11724223; PubMed Central PMCID: PMCPmc2007376.
                • 109. Comfort MB, Tse AS, Tsang AC, McGrath C. A study of the comparative efficacy of three common analgesics in the control of pain after third molar surgery under local anaesthesia. Australian dental journal. 2002;47(4):327–30. Epub 2003/02/18. pmid:12587769.
                • 110. Daniels SE, Desjardins PJ, Talwalker S, Recker DP, Verburg KM. The analgesic efficacy of valdecoxib vs. oxycodone/acetaminophen after oral surgery. Journal of the American Dental Association (1939). 2002;133(5):611–21; quiz 25. Epub 2002/05/31. pmid:12036167.
                • 111. James Fricke TV, Paul Kotey,Scott korn. ROFECOXIB COMPARED TO OXYCODONE/ACETAMINOPHEN FOR POSTOPERATIVE DENTAL PAIN. Pain Medicine. 2002;3(2):185–6.
                • 112. Garibaldi JA, Elder MF. Evaluation of ketorolac (Toradol) with varying amounts of codeine for postoperative extraction pain control. International journal of oral and maxillofacial surgery. 2002;31(3):276–80. Epub 2002/08/23. pmid:12190134.
                • 113. Fricke JR Jr., Karim R, Jordan D, Rosenthal N. A double-blind, single-dose comparison of the analgesic efficacy of tramadol/acetaminophen combination tablets, hydrocodone/acetaminophen combination tablets, and placebo after oral surgery. Clinical therapeutics. 2002;24(6):953–68. Epub 2002/07/16. pmid:12117085.
                • 114. Kiersch TA, Minic MR. The onset of action and the analgesic efficacy of Saridon (a propyphenazone/paracetamol/ caffeine combination) in comparison with paracetamol, ibuprofen, aspirin and placebo (pooled statistical analysis). Current medical research and opinion. 2002;18(1):18–25. Epub 2002/05/10. pmid:11999141.
                • 115. Macleod AG, Ashford B, Voltz M, Williams B, Cramond T, Gorta L, et al. Paracetamol versus paracetamol-codeine in the treatment of post-operative dental pain: a randomized, double-blind, prospective trial. Australian dental journal. 2002;47(2):147–51. Epub 2002/07/26. pmid:12139269.
                • 116. Joshi A, Parara E, Macfarlane TV. A double-blind randomised controlled clinical trial of the effect of preoperative ibuprofen, diclofenac, paracetamol with codeine and placebo tablets for relief of postoperative pain after removal of impacted third molars. The British journal of oral & maxillofacial surgery. 2004;42(4):299–306. Epub 2004/07/01. pmid:15225946.
                • 117. Jung YS, Kim DK, Kim MK, Kim HJ, Cha IH, Lee EW. Onset of analgesia and analgesic efficacy of tramadol/acetaminophen and codeine/acetaminophen/ibuprofen in acute postoperative pain: a single-center, single-dose, randomized, active-controlled, parallel-group study in a dental surgery pain model. Clinical therapeutics. 2004;26(7):1037–45. Epub 2004/09/01. pmid:15336468.
                • 118. Korn S, Vassil TC, Kotey PN, Fricke JR Jr. Comparison of rofecoxib and oxycodone plus acetaminophen in the treatment of acute pain: a randomized, double-blind, placebo-controlled study in patients with moderate to severe postoperative pain in the third molar extraction model. Clinical therapeutics. 2004;26(5):769–78. Epub 2004/06/29. pmid:15220020.
                • 119. Chang DJ, Bird SR, Bohidar NR, King T. Analgesic efficacy of rofecoxib compared with codeine/acetaminophen using a model of acute dental pain. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. 2005;100(4):e74–80. Epub 2005/09/27. pmid:16182156.
                • 120. Barroso AB, Lima V, Guzzo GC, Moraes RA, Vasconcellos MC, Bezerra MM, et al. Efficacy and safety of combined piroxicam, dexamethasone, orphenadrine, and cyanocobalamin treatment in mandibular molar surgery. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica [et al]. 2006;39(9):1241–7. Epub 2006/09/19. pmid:16981050.
                • 121. 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. European Journal of Oral Sciences. 2006;114(4):293–301. pmid:16911100
                • 122. Desjardins PJ, Black PM, Daniels SE, Bird SR, Petruschke RA, Chang DJ, et al. A double-blind randomized controlled trial of rofecoxib and multidose oxycodone/acetaminophen in dental impaction pain. Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons. 2007;65(8):1624–32. Epub 2007/07/28. pmid:17656293.
                • 123. Leone M, Richard O, Antonini F, Rousseau S, Chabaane W, Guyot L, et al. Comparison of methylprednisolone and ketoprofen after multiple third molar extraction: a randomized controlled study. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. 2007;103(1):e7–9. Epub 2006/12/21. pmid:17178485.
                • 124. Borel JF, Deschaumes C, Devoize L, Huard C, Orliaguet T, Dubray C, et al. [Treating pain after dental surgery: a randomised, controlled, double-blind trial to assess a new formulation of paracetamol, opium powder and caffeine versus tramadol or placebo]. Presse medicale (Paris, France: 1983). 2010;39(5):e103–11. Epub 2010/01/19. pmid:20080382.
                • 125. Merry AF, Gibbs RD, Edwards J, Ting GS, Frampton C, Davies E, et al. Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults: a randomized controlled trial. British journal of anaesthesia. 2010;104(1):80–8. Epub 2009/12/17. pmid:20007794; PubMed Central PMCID: PMCPmc2791549.
                • 126. Daniels SE, Bandy DP, Christensen SE, Boice J, Losada MC, Liu H, et al. Evaluation of the dose range of etoricoxib in an acute pain setting using the postoperative dental pain model. The Clinical journal of pain. 2011;27(1):1–8. Epub 2010/12/29. pmid:21188849.
                • 127. Isiordia-Espinoza MA, Pozos-Guillen AJ, Martinez-Rider R, Herrera-Abarca JE, Perez-Urizar J. Preemptive analgesic effectiveness of oral ketorolac plus local tramadol after impacted mandibular third molar surgery. Medicina oral, patologia oral y cirugia bucal. 2011;16(6):e776–80. Epub 2011/01/11. pmid:21217614.
                • 128. Brown JD, Daniels SE, Bandy DP, Ko AT, Gammaitoni A, Mehta A, et al. Evaluation of Multiday Analgesia With Etoricoxib in a Double-blind, Randomized Controlled Trial Using the Postoperative Third-molar Extraction Dental Pain Model. Clin J Pain. 2012. Epub 2012/12/19. pmid:23247002.
                • 129. Daniels SE, Goulder MA, Aspley S, Reader S. A randomised, five-parallel-group, placebo-controlled trial comparing the efficacy and tolerability of analgesic combinations including a novel single-tablet combination of ibuprofen/paracetamol for postoperative dental pain. Pain. 2011;152(3):632–42. Epub 2011/01/25. pmid:21257263.
                • 130. Forbes JA, Bates JA, Edquist IA, Burchfield WH, Smith FG, Schwartz MK, et al. Evaluation of Two Opioid-Acetaminophen Combinations and Placebo in Postoperative Oral Surgery Pain. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 1994;14(2):139–46.
                • 131. Forbes JA, Jones KF, Smith WK, Gongloff CM. Analgesic Effect of an Aspirin-codeine-butalbital-caffeine Combination and an Acetaminophen-codeine Combination in Postoperative Oral Surgery Pain. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 1986;6(5):240–7.