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1.  Effectiveness and tolerability of once-daily nimesulide versus ibuprofen in pain management after surgical extraction of an impacted third molar: A 24-hour, double-blind, randomized, double-dummy, parallel-group study 
Nimesulide is a nonsteroidal, anti-inflammatory drug that hasbeen used for a wide range of acute and chronic pain. A once-daily formulation of nimesulide is now commercially available, but its effectiveness in pain management after dental surgery has not been assessed.
The aim of this study was to assess the analgesic effectiveness and tolerability of oral treatment with once-daily nimesulide versus ibuprofen q6h over 24 hours in patients with postoperative pain associated with surgical extraction of an impacted third molar.
This 24-hour, double-blind, randomized, double-dummy, parallel-groupstudy was conducted at a private practice in Caracas, Venezuela. Patients aged between 12 and 60 years with moderate to severe pain after extraction of an impacted third molar were enrolled. Patients were randomized to receive a single dose of nimesulide (300-mg tablet) or ibuprofen (400-mg tablets) q6h for 24 hours. For double-dummy design, patients in the nimesulide group also received ibuprofen placebo tablets, to be taken q6h for 24 hours, and patients in the ibuprofen group received a nimesulide placebo tablet. The primary end points were pain intensity (PI) and pain relief scores over 24 hours. Secondary end points included total pain relief, PI difference (PID), sum of PID (SPID), time to first measurable change in PI (ie, PID ≥ 10 mm), and use of rescue medication (acetaminophen). Patients also rated the treatment's effectiveness as very poor to very good on questioning by the study investigator. Spontaneously reported adverse effects (AEs) were recorded.
Eighty-six patients were enrolled (56 females, 30 males), with 43 patientsper treatment group (mean age: nimesulide group, 25.2 years; ibuprofen group, 24.2 years). The baseline characteristics were statistically similar between the 2 groups. Compared with baseline, mean PI scores were significantly lower in both treatment groups at all time points throughout the study (P < 0.001). Mean PI scores were significantly lower in the nimesulide group compared with the ibuprofen group at 15 and 45 minutes and 1 hour after study drug administration (P ≤ 0.049). Time to first measurable change in PI was within the first 15 minutes in 22 patients (52%) in the nimesulide group and in 14 patients (33%) in the ibuprofen group (P = 0.03). Analgesia lasted 24 hours with nimesulide and ibuprofen (PI scores at 24 hours, 9.4 and 3.6, respectively). The mean PR score was significantly lower in the nimesulide group compared with the ibuprofen group at 1 hour after study drug administration (P = 0.049). Compared with baseline, PID and SPID were significantly higher in both treatment groups throughout the study (P < 0.001). Significantly more patients in the nimesulide group than in the ibuprofen group reported that treatment provided effective pain relief (82% vs 73%; P = 0.013). No AEs were reported in either treatment group throughout the study. Use of rescue medication was statistically similar between the nimesulide and ibuprofen groups (38% and 31%, respectively).
In this study of patients with moderate to severe pain afterextraction of impacted third molars, nimesulide and ibuprofen provided effective 24-hour relief. However, the results suggest that the analgesic effect of nimesulide had a faster onset (<15 minutes) and was stronger (based on patient opinion) than that of ibuprofen. Both study drugs were well tolerated.
PMCID: PMC3964531  PMID: 24672121
nimesulide; ibuprofen; dental pain; programmed liberation
2.  Tramadol and acetaminophen tablets for dental pain. 
Anesthesia Progress  2001;48(3):79-81.
The purpose of this work was to compare the efficacy and time to analgesia of a new tramadol/acetaminophen combination tablet to those of tramadol or acetaminophen (APAP) alone. A meta-analysis was performed of 3 separate single-dose, double-blind, parallel-group trials in patients with moderate or severe pain following extraction of 2 or more third molars. Patients in each study were evenly randomized to a single dose of tramadol/APAP (75 mg/650 mg), tramadol 75 mg, APAP 650 mg, ibuprofen 400 mg, or placebo. Active control with ibuprofen was used to determine model sensitivity. Pain relief (scale, 0-4) and pain intensity (scale, 0-3) were reported at 30 minutes after the dose and then hourly for 8 hours. Total pain relief over 8 hours (TOTPAR8) and the sum of pain intensity differences (SPID8) were calculated from the hourly scores. Time to onset of pain relief was determined by the double-stopwatch technique, and patients were advised to wait at least 2 hours before taking supplemental analgesia. Patients assessed overall efficacy (scale, 1-5) upon completion. In all, 1197 patients (age range, 16-46 years) were evaluable for efficacy; treatment groups in each study were similar at baseline. Pain relief was superior to placebo (P < or = .0001) for all treatments. Pain relief provided by tramadol/ APAP was superior to that of tramadol or APAP alone, as shown by mean TOT-PAR8 (12.1 vs 6.7 and 8.6, respectively, P < or = .0001) and SPID8 (4.7 vs 0.9 and 2.7, respectively, P < or = .0001). Estimated onset of pain relief was 17 minutes (95% CI, 15-20 minutes) for tramadol/APAP compared with 51 minutes (95% CI, 40-70 minutes) for tramadol, 18 minutes (95% CI, 16-21 minutes) for APAP, and 34 minutes (95% CI, 28-44 minutes) for ibuprofen. Median time to supplemental analgesia and mean overall assessment of efficacy were greater (P < .05) for the tramadol/APAP group (302 minutes and 3.0, respectively) than for the tramadol (122 minutes and 2.0) or APAP (183 minutes and 2.7) monotherapy groups. A new combination analgesic, tramadol/APAP, is superior to tramadol or APAP alone with respect to pain relief and duration of action. It is also superior to tramadol alone with respect to time to onset.
PMCID: PMC2007376  PMID: 11724223
3.  The Analgesic Efficacy of Preoperative Oral Ibuprofen and Acetaminophen in Children Undergoing Adenotonsillectomy: A Randomized Clinical Trial 
Adenotonsillectomy is one of the most common surgical procedures in children. Several complications and morbidities are common after nasal surgeries and the most common is pain. Several techniques have been employed to reduce the severity of postoperative pain. One of the preoperative techniques is pre-emptive analgesia through preventive central hypersensitization. This technique is performed by applying analgesic methods before the onset of nociceptive stimuli, consequently decreasing postoperative analgesics requirements.
Preoperative oral drug administration for pain analgesia is performed in several methods. The aim of this study was to compare the analgesic effects of preoperatively administration of oral acetaminophen and ibuprofen.
Patients and Methods:
In a double-blinded, randomized placebo-controlled study, sixty 4-12 years old ASA I or II children scheduled for elective adenotonsillectomy, were assigned to receive either acetaminophen 15 mg/kg, ibuprofen 10 mg/kg or placebo 30 minutes before the operation. Postoperative pain was assessed using the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS), upon arrival to the post anesthetic care unit (PACU) and ward. Findings were analyzed by SPSS version 17 using variance analysis and Tukey’s test.
The average pain intensities were significantly lower in acetaminophen group based on the CHEOPS in both PACU and ward compared to ibuprofen or placebo groups; but there was no difference in pain intensity between the ibuprofen and placebo groups. Pain intensity in PACU in Acetaminophen group was 7.05 ± 0.64 vs. 8.38 ± 1.20 in placebo group and 8.14 ± 0.85 in ibuprofen group, pain intensity in ward in the acetaminophen group was 6.0.87 ± 0.85in the acetaminophen group, vs. 8.04 ± 1.02 in placebo group, and 7.78 ± 0.78 in ibuprofen group.
This study showed that administration of oral acetaminophen 30 minutes preoperatively, resulted in significantly lower pain intensity in children undergoing adenotonsillectomy in PACU and ward, compared to ibuprofen and placebo.
PMCID: PMC3961035  PMID: 24660156
Acetaminophen; Ibuprofen; Pain, Postoperative
4.  Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial 
Objective To investigate whether paracetamol (acetaminophen) plus ibuprofen are superior to either drug alone for increasing time without fever and the relief of fever associated discomfort in febrile children managed at home.
Design Individually randomised, blinded, three arm trial.
Setting Primary care and households in England.
Participants Children aged between 6 months and 6 years with axillary temperatures of at least 37.8°C and up to 41.0°C.
Intervention Advice on physical measures to reduce temperature and the provision of, and advice to give, paracetamol plus ibuprofen, paracetamol alone, or ibuprofen alone.
Main outcome measures Primary outcomes were the time without fever (<37.2°C) in the first four hours after the first dose was given and the proportion of children reported as being normal on the discomfort scale at 48 hours. Secondary outcomes were time to first occurrence of normal temperature (fever clearance), time without fever over 24 hours, fever associated symptoms, and adverse effects.
Results On an intention to treat basis, paracetamol plus ibuprofen were superior to paracetamol for less time with fever in the first four hours (adjusted difference 55 minutes, 95% confidence interval 33 to 77; P<0.001) and may have been as good as ibuprofen (16 minutes, −7 to 39; P=0.2). For less time with fever over 24 hours, paracetamol plus ibuprofen were superior to paracetamol (4.4 hours, 2.4 to 6.3; P<0.001) and to ibuprofen (2.5 hours, 0.6 to 4.4; P=0.008). Combined therapy cleared fever 23 minutes (2 to 45; P=0.025) faster than paracetamol alone but no faster than ibuprofen alone (−3 minutes, 18 to −24; P=0.8). No benefit was found for discomfort or other symptoms, although power was low for these outcomes. Adverse effects did not differ between groups.
Conclusion Parents, nurses, pharmacists, and doctors wanting to use medicines to supplement physical measures to maximise the time that children spend without fever should use ibuprofen first and consider the relative benefits and risks of using paracetamol plus ibuprofen over 24 hours.
Trial registration Current Controlled Trials ISRCTN26362730.
PMCID: PMC2528896  PMID: 18765450
5.  Prospective, randomized, open-label, pilot clinical trial comparing the effects of dexamethasone coadministered with diclofenac potassium or acetaminophen and diclofenac potassium monotherapy after third-molar extraction in adults 
Patients who experience pain, swelling, and trismus after third-molar extraction are reported to experience a 3-fold higher rate of adverse effects (AEs) on quality of life compared with those who are asymptomatic after this surgery. Therefore, investigators emphasize the necessity for better control of this triad of sequelae. Steroids can reduce the risk for physiologic processes of inflammation, thereby suppressing the development of inflammation.
The aim of this study was to compare the effects of dexamethasone 8 mg IM and diclofenac potassium (K) 50 mg PO, dexamethasone 8 mg IM and acetaminophen 1000 mg PO, and monotherapy with diclofenac K 50 mg PO on postoperative pain, swelling, and trismus after surgical removal of third molars.
This prospective, randomized, open-label pilot study was conducted at the Department of Oral and Maxillofacial Surgery, Lagos University Teaching Hospital, Lagos, Nigeria. Patients were randomly allocated to 1 of 3 treatment groups: concomitant treatment with dexamethasone 8 mg IM and diclofenac K 50 mg PO or acetaminophen 1000 mg PO, or monotherapy with diclofenac K 50 mg PO. Overall analgesic efficacy of the drug combinations was assessed for 7 days postoperatively using a 4-point categorical pain-intensity rating scale (0 = no pain; 1 = mild pain; 2 = moderate pain; and 3 = severe pain). Facial swelling was measured in 1 dimension on days 1, 2, and 7 after surgery using a tape measure placed from the tip of the tragus, to gonion, to the tip of the contralateral tragus, and trismus was assessed using interincisal mouth-opening ability, measured using a vernier-calibrated caliper on postoperative days 1, 2, and 7. Tolerability was assessed using direct questioning of the patients at follow-up visits.
A total of 150 patients (50 per treatment group) were included in the analysis (76 women, 74 men; mean [SD] age, 26.8 [5.04] years [range, 18–45 years]; 100% Nigerian). The proportion of patients reporting no pain on the pain-intensity rating scale was significantly higher in the group receiving dexamethasone and diclofenac K compared with that in the groups receiving dexamethasone and acetaminophen or diclofenac K monotherapy (44% vs 22% and 24%, respectively; both, P < 0.05). Facial swelling was significantly less with dexamethasone and diclofenac K or dexamethasone and acetaminophen compared with diclofenac K alone (day 1: P = 0.013 and P = 0.011, respectively; day 2: P = 0.002 and P = 0.004, respectively). However, trismus relief was statistically similar between the 3 treatment groups on postoperative days 1 and 2. No AEs or complications were recorded.
In this open-label pilot study, concomitant treatment with dexamethasone and diclofenac K provided significant relief of postsurgical pain and swelling compared with dexamethasone and acetaminophen or monotherapy with diclofenac K after third-molar extraction in these patients.
PMCID: PMC3965982  PMID: 24678099
dexamethasone; diclofenac potassium; acetaminophen; third-molar extraction
6.  Ibuprofen with or without an antiemetic for acute migraine headaches in adults 
Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers do not seek professional help, relying instead on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce symptoms commonly associated with migraine headaches.
To determine efficacy and tolerability of ibuprofen, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults.
Search methods
We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 22 April 2010.
Selection criteria
We included randomised, double-blind, placebo- or active-controlled studies using self-administered ibuprofen to treat a migraine headache episode, with at least 10 participants per treatment arm.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and number needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment.
Main results
Nine studies (4373 participants, 5223 attacks) compared ibuprofen with placebo or other active comparators; none combined ibuprofen with a self-administered antiemetic. All studies treated attacks with single doses of medication. For ibuprofen 400 mg versus placebo, NNTs for 2-hour pain-free (26% versus 12% with placebo), 2-hour headache relief (57% versus 25%) and 24-hour sustained headache relief (45% versus 19%) were 7.2, 3.2 and 4.0, respectively. For ibuprofen 200 mg versus placebo, NNTs for 2-hour pain-free (20% versus 10%) and 2-hour headache relief (52% versus 37%) were 9.7 and 6.3, respectively. The higher dose was significantly better for 2-hour headache relief than the lower dose. Soluble formulations of ibuprofen 400 mg were better than standard tablets for 1-hour, but not 2-hour headache relief.
Associated symptoms of nausea, vomiting, photophobia and phonophobia and functional disability were reduced within 2 hours, and fewer participants used rescue medication with ibuprofen compared with placebo. Similar numbers of participants experienced adverse events, which were mostly mild and transient.
Ibuprofen 400 mg did not differ from rofecoxib 25 mg for 2-hour headache relief, 24-hour headache relief or use of rescue medication.
Authors’ conclusions
Ibuprofen is an effective treatment for acute migraine headaches, providing pain relief in about half of sufferers, but complete relief from pain and associated symptoms for only a minority. NNTs for all efficacy outcomes were better with 400 mg than 200 mg in comparisons with placebo, and soluble formulations provided more rapid relief. Adverse events were mostly mild and transient, occurring at the same rate as with placebo.
PMCID: PMC4161114  PMID: 20927770
Administration, Oral; Analgesics, Non-Narcotic [* therapeutic use]; Antiemetics [* therapeutic use]; Drug Therapy, Combination [methods]; Ibuprofen [* therapeutic use]; Migraine Disorders [* drug therapy]; Randomized Controlled Trials as Topic; Adult; Humans
7.  Comparison of the effects of ibuprofen and acetaminophen on PGE2 levels in the GCF during orthodontic tooth movement: a human study 
Progress in Orthodontics  2013;14(1):6.
Pain is among the most cited negative effects of orthodontic treatment. Non-steroidal anti-inflammatory drugs seem to be an effective option for minimizing this but can have adverse effects on tooth movement owing to their ability to block prostaglandin synthesis. Acetaminophen has been suggested as the analgesic of choice during orthodontic treatment as it showed no effect on orthodontic tooth movement in previous animal studies. The purpose of this study was to compare the effects of ibuprofen and acetaminophen on the prostaglandin E2 (PGE2) levels of the gingival crevicular fluid (GCF) during orthodontic tooth movement in human subjects.
A total of 42 patients (mean age 18 ± 4.5 years) were randomly divided into three equal groups: ibuprofen, acetaminophen, and control groups. Maxillary canines were distalized with 150 g of force delivered by NiTi coil springs. GCF samples were obtained before (baseline) and after spring activation at 24, 48, and 168 h. The PGE2 content of the GCF was determined using enzyme-linked immunosorbent assay.
PGE2 levels in all groups increased significantly by 24 and 48 h of force application and decreased to baseline levels by 168 h. No significant difference was found between the acetaminophen and control groups at any time point. There was a significant decrease in PGE2 levels in the ibuprofen group at 24 and 48 h when compared to the other two groups.
Acetaminophen showed no significant effect on prostaglandin synthesis and may be the safe choice compared to ibuprofen for relieving pain associated with orthodontic tooth movement.
PMCID: PMC3847847  PMID: 24325834
8.  DUEXIS® (ibuprofen 800 mg, famotidine 26.6 mg): a new approach to gastroprotection for patients with chronic pain and inflammation who require treatment with a nonsteroidal anti-inflammatory drug 
Chronic pain conditions affect at least 116 million US adults and more than one-third of adults worldwide. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively for the treatment of chronic pain due to their efficacy as anti-inflammatory and analgesic agents. Gastrointestinal toxicity is the most well known adverse effect of NSAID therapy and it may manifest as dyspepsia, ulcers, or bleeding. Current guidelines for the management of patients who require NSAIDs for chronic pain and inflammation recognize the potential toxicity associated with these drugs and the need for gastroprotection. DUEXIS® (ibuprofen 800 mg, famotidine 26.6 mg) is a proprietary combination, immediate release tablet containing 800 mg of ibuprofen and 26.6 mg of famotidine. The efficacy of DUEXIS® taken three times daily has been demonstrated in two large-scale controlled clinical trials (Registration Endoscopic Studies to Determine Ulcer Formation of HZT-501 Compared with Ibuprofen: Efficacy and Safety Studies (REDUCE) and REDUCE-2) which showed that this new formulation significantly reduced the risk of endoscopic upper gastrointestinal ulcers compared with ibuprofen alone (REDUCE-1, p < 0.0001, REDUCE-2, p <0.05). DUEXIS® was also superior to ibuprofen in decreasing the risk for gastric ulcers (REDUCE-1, p < 0.001, REDUCE-2, p < 0.05) as well as duodenal ulcers (REDUCE-1, p < 0.05, REDUCE-2, p < 0.05). Safety results from these two studies indicated that treatment-emergent adverse events occurred in 55% of patients treated with DUEXIS® versus 58.7% for ibuprofen, and serious adverse events were recorded for 3.2% of patients treated with DUEXIS® versus 3.3% of those on ibuprofen. Adverse events leading to discontinuation occurred in 6.7% of patients treated with DUEXIS® and 7.6% for ibuprofen. The combination of ibuprofen and famotidine in a single tablet has the potential to improve adherence to gastroprotective therapy in patients who require NSAID treatment and the use of a histamine type 2 receptor antagonist rather than a proton-pump inhibitor may decrease the risk for clinically significant drug interactions and adverse events (e.g. interaction with clopidogrel, fracture, pneumonia, Clostridium difficile infection).
PMCID: PMC3458616  PMID: 23024710
chronic pain; famotidine; gastrointestinal; ibuprofen; proton-pump inhibitor; ulcer
9.  The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol 
Ibuprofen and paracetamol differ in their mode of action and related therapeutic effects, suggesting that combined administration may offer improved analgesia. Reported here are the results of two studies on the pharmacokinetic properties of a novel ibuprofen (200 mg) and paracetamol (500 mg) fixed-dose combination tablet.
Both studies were open-label, randomised studies in healthy volunteers: Study 1 was a four-way crossover, single-dose study; Study 2 was a two-way cross-over, repeat-dose study.
Pharmacokinetic parameters for ibuprofen and paracetamol were similar for the combination and monotherapy tablets (values falling within the 80% to 125% acceptable bioequivalence range) except for the rate of absorption of paracetamol from the combination (tmax), which was significantly faster compared with monotherapy (median difference 10 minutes; p < 0.05). Mean plasma concentrations of both drugs were higher, earlier, following administration of the combination tablet compared with monotherapy. Mean plasma levels at 10 and 20 minutes were 6.64 μg.mL-1 and 16.81 μg.mL-1, respectively, for ibuprofen from the combination, compared with 0.58 μg.mL-1 and 9.00 μg.mL-1, respectively, for monotherapy. For paracetamol, mean plasma levels at 10 and 20 minutes were 5.43 μg.mL-1 and 14.54 μg.mL-1, respectively, for the combination compared with 0.33 μg.mL-1 and 9.19 μg.mL-1, respectively, for monotherapy. The rate of absorption of both ibuprofen and paracetamol was significantly delayed when the combination tablet was administered in the fed versus fasted state; median delay was 25 minutes for ibuprofen (p > 0.05) and 55 minutes for paracetamol (p < 0.001). The pharmacokinetic parameters were comparable irrespective of whether the combination tablet was given twice or three times daily; systemic exposure was, however, approximately 1.4 times greater for both drugs when given three times daily.
Administration of ibuprofen and paracetamol in a fixed-dose combination tablet does not significantly alter the pharmacokinetic profiles of either drug, except for enhancing the rate of paracetamol absorption, offering potential therapeutic benefits in relation to the onset of analgesia. Concentrations of both drugs reached previously reported therapeutic levels when the combination tablet was administrated in the fed or fasted state. Three times daily dosing may offer enhanced therapeutic effect for longer than twice daily dosing.
PMCID: PMC2906415  PMID: 20602760
10.  Efficacy of Standard Doses of Ibuprofen Alone, Alternating, and Combined With Acetaminophen for the Treatment of Febrile Children 
Clinical therapeutics  2010;32(14):2433-2440.
Many pediatricians recommend, and many parents administer, alternating or combined doses of ibuprofen and acetaminophen for fever. Limited data support this practice with standard US doses.
This study compared the antipyretic effect of 3 different treatment regimens in children, using either ibuprofen alone, ibuprofen combined with acetaminophen, or ibuprofen followed by acetaminophen over a single 6-hour observation period.
Febrile episodes from children aged 6 to 84 months were randomized into the 3 treatment groups: a single dose of ibuprofen at the beginning of the observation period; a single dose of ibuprofen plus a single dose of acetaminophen at the beginning of the observation period; or ibuprofen followed by acetaminophen 3 hours later. Ibuprofen was administered at 10 mg/kg; acetaminophen at 15 mg/kg. Temperatures were measured hourly for 6 hours using a temporal artery thermometer. The primary outcome was temperature difference between treatment groups. Adverse-event data were not collected in this single treatment period study.
Sixty febrile episodes in 46 children were assessed. The mean (SD) age of the children was 3.4 (2.2) years, and 31 (51.7%) were girls. Differences among temperature curves were significant (P < 0.001; the combined and alternating arms had significantly better antipyresis compared with the ibuprofen-alone group at hours 4 to 6 (hour 4, P < 0.005; hours 5 and 6, P < 0.001). All but one of the children in the combined and alternating groups were afebrile at hours 4, 5, and 6. In contrast, for those receiving ibuprofen alone, 30%, 40%, and 50% had temperatures >38.0°C at hours 4, 5, and 6, respectively (hour 4, P < 0.002; hours 5 and 6, P < 0.001).
During a single 6-hour observation period for these participating children, combined and alternating doses of ibuprofen and acetaminophen provided greater antipyresis than ibuprofen alone at 4 to 6 hours.
PMCID: PMC3614072  PMID: 21353111
fever; antipyretic; acetaminophen; ibuprofen
11.  Two-agent analgesia versus acetaminophen in children having bilateral myringotomies and tubes surgery 
Paediatric anaesthesia  2010;20(11):1028-1035.
The objective of this study was to determine whether the incidence of emergence agitation (EA) can be reduced by adding an additional, faster onset, non-IV analgesic, intranasal fentanyl or intramuscular (im) ketorolac to rectal acetaminophen.
To compare the incidence of EA after analgesia with two agents vs acetaminophen alone in pediatric patients after bilateral myringotomy procedures (BM&T).
Anesthesia for BM&T is usually performed with volatile anesthetics as a single agent without securing intravenous access. The anesthetic agent most commonly used is sevoflurane; however, EA has been reported in up to 67% of patients. Emergence agitation is distressing for parents, can impair the ability of nursing staff to adequately monitor the child, and can result in a child injuring him/herself if it is severe.
A standardized anesthetic was used with oral midazolam premedication and sevoflurane for induction, and maintenance of anesthesia. All patients received 40 mg·kg−1 rectal acetaminophen, group 1 received acetaminophen alone, group 2 received acetaminophen and 1 mcg·kg−1 of intranasal fentanyl, and group 3 received acetaminophen and 1 mg·kg−1 of intramuscular ketorolac. Incidence of EA was compared using chi-square test between the acetaminophen group alone vs the two-agent analgesia groups combined.
There were no differences in demographic and clinical characteristics between the two groups. There were no statistically significant differences between the three groups for the incidence of EA at any time point during recovery from anesthesia nor were there any significant differences in pain scores or side effects. No significant side effects because of the administration of a second analgesic agent were reported.
We conclude that two-agent analgesia is not superior to acetaminophen alone for decreasing the incidence of EA after inhalation anesthesia with sevoflurane for BM&T surgery. Our overall incidence of EA was low compared to previous studies, which could potentially have decreased our ability to detect differences between groups.
PMCID: PMC4005868  PMID: 20964769
ear tube surgery; children; postoperative analgesia; emergence agitation; intranasal fentanyl; intramuscular ketorolac
12.  Prophylactic Use of Oral Acetaminophen or IV Dexamethasone and Combination of them on Prevention Emergence Agitation in Pediatric after Adenotonsillectomy 
The present study was aimed to evaluate the efficacy of acetaminophen plus dexamethasone on post-operative emergence agitation in pediatric adenotonsillectomy.
A total of 128 patients were randomized and assigned among four groups as: Intravenous (IV) dexamethasone, oral acetaminophen, IV dexamethasone plus oral acetaminophen, placebo. Group 1 received 0.2 mg/kg dexamethasone plus 0.25 mg/kg strawberry syrup 2 h before surgery. Group 2 received 20 mg/kg oral acetaminophen (0.25 ml/kg) with 0.05 ml/kg IV normal saline. Group 3 received 20 mg/kg acetaminophen and 0.2 mg/kg dexamethasone intravenously. Group 4 received 0.25 ml/kg strawberry syrup and 0.05 ml/kg normal saline. Agitation was measured according to Richmond agitation sedation score in the post anesthetic care unit (PACU) after admission, 10, 20 and 30 min after extubation. Pain score was measured with FACE scale. Nurse satisfaction was measured with verbal analog scale. If agitation scale was 3 ≥ or pain scale was 4 ≥ meperidine was prescribed. If symptoms did not control wit in 15 min midazolam was prescribed. Patients were discharged from PACU according Modified Alderet Score. Data were analyzed with ANOVA, Chi-square, and Kruskal-Wallis among four groups. P < 0.05 was considered statistically significant.
A total of 140 patients were recruited in the study, which 12 of them were excluded. Thus, 128 patients were randomized and assigned among four groups. The four treatment groups were generally matched at baseline data. Median of pain score in 0, 10, 20 and 30 min after extubation were different between each study group with the control group (<0.001, 0.003 respectively). Also median of agitation score in 0, 10, 20 and 30 min after extubation were different between each study group with the control group (<0.001). Incidence of pain and incidence of agitation after extubation were not statistically identical among groups (P < 0.001 and P = 0.002 respectively). Mean of recovery time, duration of agitation and 1st time to agitation appearance, meperidine and midazolam consumption, nurse satisfaction and complication frequency were not statistically identical among groups (P < 0.001).
Acetaminophen, dexamethasone and combination of them are superior to placebo for prevention of agitation after adenotonsillectomy in children. Furthermore combinations of both drugs are superior to acetaminophen or dexamethasone separately.
PMCID: PMC4085924  PMID: 25013691
Acetaminophen; adenotonsillectomy; dexamethasone; postoperative agitation
13.  Single dose oral analgesics for acute postoperative pain in adults 
Thirty-five Cochrane Reviews of randomised trials testing the analgesic efficacy of individual drug interventions in acute postoperative pain have been published. This overview brings together the results of all those reviews and assesses the reliability of available data.
To summarise data from all Cochrane Reviews that have assessed the effects of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery, who have been given a single dose of oral analgesic taken alone.
We identified systematic reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single Review Group, had a standard title, and had as their primary outcome numbers of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews we extracted the number needed to treat (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, the percentage of participants remedicating by 6, 8, 12, or 24 hours, and results for participants experiencing at least one adverse event.
Main results
The overview included 35 separate Cochrane Reviews with 38 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 45,000 participants studied in approximately 350 individual studies. The individual reviews included only high-quality trials of standardised design and outcome reporting. The reviews used standardised methods and reporting for both efficacy and harm. Event rates with placebo were consistent in larger data sets. No statistical comparison was undertaken.
There were reviews but no trial data were available for acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for dexibuprofen, dextropropoxyphene 130 mg, diflunisal 125 mg, etoricoxib 60 mg, fenbufen, and indometacin. Where there was adequate information for drug/dose combinations (at least 200 participants, in at least two studies), we defined the addition of four comparisons of typical size (400 participants in total) with zero effect as making the result potentially subject to publication bias and therefore unreliable. Reliable results were obtained for 46 drug/dose combinations in all painful postsurgical conditions; 45 in dental pain and 14 in other painful conditions.
NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours in the same pain condition. Participants reporting at least one adverse event were few and generally no different between active drug and placebo, with a few exceptions, principally for aspirin and opioids.
Drug/dose combinations with good (low) NNTs were ibuprofen 400 mg (2.5; 95% confidence interval (CI) 2.4 to 2.6), diclofenac 50 mg (2.7; 95% CI 2.4 to 3.0), etoricoxib 120 mg (1.9; 95% CI 1.7 to 2.1), codeine 60 mg + paracetamol 1000 mg (2.2; 95% CI 1.8 to 2.9), celecoxib 400 mg (2.5; 95% CI 2.2 to 2.9), and naproxen 500/550 mg (2.7; 95% CI 2.3 to 3.3). Long duration of action (8 hours) was found for etoricoxib 120 mg, diflunisal 500 mg, oxycodone 10 mg + paracetamol 650 mg, naproxen 500/550 mg, and celecoxib 400 mg.
Not all participants had good pain relief and for many drug/dose combinations 50% or more did not achieve at last 50% maximum pain relief over four to six hours.
Authors’ conclusions
There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers.
PMCID: PMC4160790  PMID: 21901726
Administration, Oral; Analgesics [*administration & dosage; adverse effects]; Pain, Postoperative [*drug therapy]; Review Literature as Topic; Tooth Extraction [adverse effects]; Adult; Humans
14.  Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S-(+)- and R-(−)-Ibuprofen 
Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(+)- and R-(−)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations of S-(+)- and R-(−)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) of S-(+)-ibuprofen was 205% (P < 0.001) of the respective control value and the mean peak plasma concentration (Cmax) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t1/2) was prolonged from 2.4 to 3.2 h (P < 0.01) by voriconazole. In the fluconazole phase, the mean AUC of S-(+)-ibuprofen was 183% of the control value (P < 0.001) and its mean Cmax was 116% of the control value (P < 0.05). The mean t1/2 of S-(+)-ibuprofen was prolonged from 2.4 to 3.1 h (P < 0.05) by fluconazole. The geometric mean S-(+)-ibuprofen AUC ratios in the voriconazole and fluconazole phases were 2.01 (90% confidence interval [CI], 1.80 to 2.22) and 1.82 (90% CI, 1.72 to 1.91), respectively, i.e., above the bioequivalence acceptance upper limit of 1.25. Voriconazole and fluconazole had only weak effects on the pharmacokinetics of R-(−)-ibuprofen. In conclusion, voriconazole and fluconazole increased the levels of exposure to S-(+)-ibuprofen 2- and 1.8-fold, respectively. This was likely caused by inhibition of the cytochrome P450 2C9-mediated metabolism of S-(+)-ibuprofen. A reduction of the ibuprofen dosage should be considered when ibuprofen is coadministered with voriconazole or fluconazole, especially when the initial ibuprofen dose is high.
PMCID: PMC1479148  PMID: 16723553
15.  Alternating ibuprofen and acetaminophen in the treatment of febrile children: a pilot study [ISRCTN30487061] 
BMC Medicine  2006;4:4.
Alternating ibuprofen and acetaminophen for the treatment of febrile children is a prevalent practice among physicians and parents, despite the lack of evidence on effectiveness or safety. This randomized, double-blind and placebo-controlled clinical trial aims at comparing the antipyretic effectiveness and safety of a single administration of alternating ibuprofen and acetaminophen doses to that of ibuprofen mono-therapy in febrile children.
Seventy febrile children were randomly allocated to receive either a single oral dose of 10 mg/kg ibuprofen and 15 mg/kg oral acetaminophen after 4 hours, or a similar dose of ibuprofen and placebo at 4 hours. Rectal temperature was measured at baseline, 4, 5, 6, 7 and 8 hours later. Endpoints included proportions of afebrile children at 6, 7 and 8 hours, maximum decline in temperature, time to recurrence of fever, and change in temperature from baseline at each time point. Intent-to-treat analysis was planned with statistical significance set at P < 0.05.
A higher proportion of subjects in the intervention group (83.3%) became afebrile at 6 hours than in the control group (57.6%); P = 0.018. This difference was accentuated at 7 and 8 hours (P < 0.001) with a significantly longer time to recurrence of fever in the intervention group (mean ± SD of 7.4 ± 1.3 versus 5.7 ± 2.2 hours), P < 0.001. Odds ratios (95%CI) for defervescence were 5.6 (1.3; 23.8), 19.5 (3.5; 108.9) and 15.3 (3.4; 68.3) at 6, 7 and 8 hours respectively. Two-way ANOVA with repeated measures over time revealed a significantly larger decline in temperature in the intervention group at times 7 (P = 0.026) and 8 (P = 0.002) hours.
A single dose of alternating ibuprofen and acetaminophen appears to be a superior antipyretic regimen than ibuprofen mono-therapy. Further studies are needed to confirm these findings.
PMCID: PMC1421419  PMID: 16515705
16.  Ibuprofen versus acetaminophen with codeine for the relief of perineal pain after childbirth: a randomized controlled trial 
Pain from episiotomy or tearing of perineal tissues during childbirth is often poorly treated and may be severe. This randomized double-blind controlled trial was performed to compare the effectiveness, side effects and cost of, and patient preference for, 2 analgesics for the management of postpartum perineal pain.
A total of 237 women who gave birth vaginally with episiotomy or a third- or fourth-degree tear between August 1995 and November 1996 at a tertiary-level teaching and referral centre for obstetric care in Vancouver were randomly assigned to receive either ibuprofen (400 mg) (n = 127) or acetaminophen (600 mg) with codeine (60 mg) and caffeine (15 mg) (Tylenol No. 3) (n = 110), both given orally every 4 hours as necessary. Pain ratings were recorded before the first dose and at 1, 2, 3, 4, 12 and 24 hours after the first dose on a 10-cm visual analogue scale. Side effects and overall opinion were assessed at 24 hours.
Ibuprofen and acetaminophen with codeine had similar analgesic properties in the first 24 hours post partum (mean pain rating 3.4 and 3.3, mean number of doses in 24 hours 3.4 and 3.3, and proportion of treatment failures 13.8% [16/116] and 16.0% [16/100] respectively). Significantly fewer subjects in the ibuprofen group than in the acetaminophen with codeine group experienced side effects (52.4% v. 71.7%) (p = 0.006). There were no significant differences in overall patient satisfaction between the 2 groups. The major determinant of pain intensity was forceps-assisted delivery. Overall, 78% of the treatment failures were in women with forceps-assisted deliveries.
Since the 2 analgesics were rated similarly, ibuprofen may be the preferred choice because it is less expensive and requires less nursing time to dispense. Further studies need to address improved analgesia for women with forceps-assisted deliveries.
PMCID: PMC81582  PMID: 11706909
17.  Use of ibuprofen and risk of Parkinson disease 
Neurology  2011;76(10):863-869.
Neuroinflammation may contribute to the pathogenesis of Parkinson disease (PD). Use of nonsteroidal anti-inflammatory drugs (NSAID) in general, and possibly ibuprofen in particular, has been shown to be related to lower PD risk in previous epidemiologic studies.
We prospectively examined whether use of ibuprofen or other NSAIDs is associated with lower PD risk among 136,197 participants in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) free of PD at baseline (1998 for NHS and 2000 for HPFS). NSAIDs use was assessed via questionnaire. Results were combined in a meta-analysis with those of published prospective investigations.
We identified 291 incident PD cases during 6 years of follow-up. Users of ibuprofen had a significantly lower PD risk than nonusers (relative risk [RR], adjusted for age, smoking, caffeine, and other covariates = 0.62; 95% confidence interval [CI] 0.42–0.93; p = 0.02). There was a dose–response relationship between tablets of ibuprofen taken per week and PD risk (p trend = 0.01). In contrast, PD risk was not significantly related to use of aspirin (RR = 0.99; 95% CI 0.78–1.26), other NSAIDs (RR = 1.26; 95% CI 0.86–1.84), or acetaminophen (RR = 0.86; 95% CI 0.62–1.18). Similar results were obtained in the meta-analyses: the pooled RR was 0.73 (95% CI 0.63–0.85; p < 0.0001) for ibuprofen use, whereas use of other types of analgesics was not associated with lower PD risk.
The association between use of ibuprofen and lower PD risks, not shared by other NSAIDs or acetaminophen, suggests ibuprofen should be further investigated as a potential neuroprotective agent against PD.
PMCID: PMC3059148  PMID: 21368281
18.  Comparison of preemptive analgesic effects of a single dose of nonopioid analgesics for pain management after ambulatory surgery: A prospective, randomized, single-blind studyin Turkish patients 
Preemptive analgesia used for postsurgical pain management has been shown to reduce the requirements of postoperative analgesics.
The aim of this study was to compare the preemptive analgesic effects of diflunisal, naproxen sodium, meloxicam, acetaminophen, and rofecoxin (no longer available in some markets) in patients undergoing ambulatory dental surgery and the need for postoperative pain management in these patients.
This prospective, randomized, single-blind study was conducted at the Departments of Anesthesiology and Reanimation and Oral and Maxillofacial Surgery, Baskent University, Adana Teaching and Medical Research Center, Adana, Turkey. Turkish outpatients aged ≥ 16 years with American Society of Anesthesiologists physical status 1 (ie, healthy) and scheduled to undergo surgical extraction of an impacted third molar were enrolled. Patients were randomly assigned to receive diflunisal 500 mg, naproxen sodium 550 mg, meloxicam 7.5 mg, acetaminophen 500 mg, or rofecoxib 12.5 mg. All medications were administered orally 1 hour before surgery as preemptive analgesia and after surgery if needed, up to the maximum recommended dose. Surgery was performed with the patient under local anesthesia (articaine hydrochloride). Pain intensity was assessed using a 100-mm visual analog scale (VAS) (0 = none to 100 = worst possible pain) at 2, 4, 6, and 12 hours after ambulatory surgery. The use of additional analgesics was recorded for 24 hours using patient diaries. Postoperative adverse events were recorded using the diaries.
One hundred fifty patients (108 women, 42 men; mean [SE] age, 26.8 [0.6] years; 30 patients per group) had data available for analysis. Demographic data were similar between the 5 groups. No significant differences in mean VAS scores were found between the 5 groups at any time point. All mean VAS scores indicated minor pain. The rate of additional postoperative analgesics required was significantly lower in the diflunisal group compared with groups receiving naproxen sodium, meloxicam, acetaminophen, and rofecoxib (3 [10%] patients vs 11 [37%], 15 [50%], 15 [50%], and 14 [47%] patients, respectively; all, P < 0.05). Bleeding at the surgical site was reported in 2 patients each in the diflunisal, naproxen sodium, meloxicam, and acetaminophen groups, and in 1 patient in the rofecoxib group; the between-group differences were not significant. No significant differences in the prevalences of other adverse effects (eg, nausea, vomiting, allergy, gastrointestinal symptoms) were found between the 5 treatment groups.
In the present study in patients undergoing third molar extraction, adequate preemptive analgesia, based on VAS scores, was found with all of the nonopioid analgesic agents used. Fewer patients required rescue medication with diflunisal. All 5 study drugs were similarly well tolerated.
PMCID: PMC3966011  PMID: 24678075
preemptive analgesia; ambulatory surgery; NSAIDs
19.  Efficacy of Low Dose Combination Analgesics: Acetaminophen/Codeine, Aspirin/Butalbital/Caffeine/Codeine, and Placebo in Oral Surgery Pain 
Anesthesia Progress  1986;33(3):143-146.
A double-blind, randomized, single-dose study was performed to compare the efficacy and safety of two commonly prescribed combination analgesic products to placebo. The combinations were acetaminophen 300 mg/codeine 30 mg†, and aspirin 325 mg/butalbital 50 mg/caffeine 40 mg/codeine 30 mg††. One hundred twenty-three (123) oral surgery outpatients took study medications when their pain became moderate to severe and recorded the levels of pain intensity, pain relief, anxiety and relaxation at 30 minutes and hourly for 6 hours after dosing. Remedication was permitted if study medications did not provide adequate pain relief. Time to remedication, and the number of observations with 50% or better relief, were noted as were any side effects. An overall evaluation was obtained from each patient. Results of the study showed that the aspirin/butalbital/caffeine/codeine combination was significantly more effective than placebo for total pain relief, peak relief and global evaluation. While the acetaminophen/codeine combination was numerically superior to placebo, it achieved statistical significance only for global evaluation. The aspirin/butalbital/caffeine/codeine combination was numerically superior to acetaminophen/codeine for every measure of analgesic efficacy but the differences did not achieve statistical significance. Both active treatment groups experienced significantly less total anxiety than did the placebo group. Only 11 patients reported mild, transient adverse effects; the most common was drowsiness. The adverse effects occurred equally among the three treatment groups. In this study, the aspirin/butalbital/caffeine/codeine combination was significantly superior to placebo and somewhat better than acetaminophen/codeine.
PMCID: PMC2175477  PMID: 3461726
20.  Effects of naloxone and flumazenil on antinociceptive action of acetaminophen in rats 
Background: Studies of acetaminophen suggest that multiple nociceptive pathways are involved in the drug's analgesic action.
Objective: The purpose of this study was to determine whether naloxone and flumazenil were able to modify or antagonize the antinociceptive effect of acetaminophen in rats.
Methods: Adult albino Wistar rats were used in the study and randomly allocated to 1 of 4 groups. The acetaminophen group (A group) was administered IP saline and then 300 mg/kg IP acetaminophen 5 minutes thereafter. The acetaminophen + naloxone group (AN group) was pretreated with 1 mg/kg IP naloxone, followed by 300 mg/kg IP acetaminophen 5 minutes later. The acetaminophen + flumazenil group (AF group) was pretreated with 1 mg/kg IP flumazenil, followed by 300 mg/kg IP acetaminophen 5 minutes later. The control group received 2.5 mL IP saline, followed by an additional 2.5 mL IP injection of saline 5 minutes later. The paw-withdrawal latency period of the rats was assessed by an investigator blinded to treatment using the hot-plate test at 30, 45, 60, and 90 minutes after administration of acetaminophen.
Results: Thirty-two rats were evenly randomized by envelope method into 4 groups of 8 rats each. Baseline values for the A, AN, AF, and control groups were not significantly different (9.1 [2.3], 10.5 [2.7], 9.8 [3.0], and 8.9 [1.4] sec, respectively). In the AF group, flumazenil appeared to antagonize the analgesic effect exerted by the acetaminophen in the hot-plate test (30 min, 10.3 [3.7] sec; 45 min, 11.7 [5.1] sec; 60 min, 12.1 [5.1] sec; and 90 min, 12.2 [4.9] sec) and values were not significantly different from those obtained in the control group (30 min, 9.8 [2.2] sec; 45 min, 9.0 [1.6] sec; 60 min, 9.2 [1.6] sec; and 90 min, 8.5 [2.0] sec). In the AN group, naloxone did not significantly affect the values observed in the hot-plate test (30 min, 18.0 [4.5] sec; 45 min, 21.5 [7.8] sec; 60 min, 20.5 [5.9] sec; and 90 min, 22.3 [7.4] sec) and values at all time points were not significantly different from those obtained in the A group (30 min, 17.8 [7.6] sec; 45 min, 20.9 [6.9] sec; 60 min, 21.5 [7.3] sec; and 90 min, 23.8 [8.6] sec). All postbaseline values in the A and AN groups were significantly increased versus baseline and versus the control group values (all, P < 0.05). All postbaseline values in the A group were significantly greater than those in the AF group (all, P < 0.05).
Conclusion: Flumazenil antagonized the analgesic effect exerted by acetaminophen, while naloxone had no significant effect on acetaminophen's antinociceptive action in this pain model in rats.
PMCID: PMC3967277  PMID: 24683257
antinociceptive action; acetaminophen (paracetamol); flumazenil; naloxone
21.  Oral administration of morphine versus ibuprofen to manage postfracture pain in children: a randomized trial 
Recent warnings from Health Canada regarding codeine for children have led to increased use of nonsteroidal anti-inflammatory drugs and morphine for common injuries such as fractures. Our objective was to determine whether morphine administered orally has superior efficacy to ibuprofen in fracture-related pain.
We used a parallel group, randomized, blinded superiority design. Children who presented to the emergency department with an uncomplicated extremity fracture were randomly assigned to receive either morphine (0.5 mg/kg orally) or ibuprofen (10 mg/kg) for 24 hours after discharge. Our primary outcome was the change in pain score using the Faces Pain Scale — Revised (FPS-R). Participants were asked to record pain scores immediately before and 30 minutes after receiving each dose.
We analyzed data from 66 participants in the morphine group and 68 participants in the ibuprofen group. For both morphine and ibuprofen, we found a reduction in pain scores (mean pre–post difference ± standard deviation for dose 1: morphine 1.5 ± 1.2, ibuprofen 1.3 ± 1.0, between-group difference [δ] 0.2 [95% confidence interval (CI) −0.2 to 0.6]; dose 2: morphine 1.3 ± 1.3, ibuprofen 1.3 ± 0.9, δ 0 [95% CI −0.4 to 0.4]; dose 3: morphine 1.3 ± 1.4, ibuprofen 1.4 ± 1.1, δ −0.1 [95% CI −0.7 to 0.4]; and dose 4: morphine 1.5 ± 1.4, ibuprofen 1.1 ± 1.2, δ 0.4 [95% CI −0.2 to 1.1]). We found no significant differences in the change in pain scores between morphine and ibuprofen between groups at any of the 4 time points (p = 0.6). Participants in the morphine group had significantly more adverse effects than those in the ibuprofen group (56.1% v. 30.9%, p < 0.01).
We found no significant difference in analgesic efficacy between orally administered morphine and ibuprofen. However, morphine was associated with a significantly greater number of adverse effects. Our results suggest that ibuprofen remains safe and effective for outpatient pain management in children with uncomplicated fractures. Trial registration:, no. NCT01690780.
PMCID: PMC4259768  PMID: 25349008
22.  Single dose oral ibuprofen for acute postoperative pain in adults 
This review updates a 1999 Cochrane review showing that ibuprofen at various doses was effective in postoperative pain in single dose studies designed to demonstrate analgesic efficacy. New studies have since been published. Ibuprofen is one of the most widely used non-steroidal anti-inflammatory (NSAID) analgesics both by prescription and as an over-the-counter medicine. Ibuprofen is used for acute and chronic painful conditions.
To assess analgesic efficacy of ibuprofen in single oral doses for moderate and severe postoperative pain in adults.
Search methods
We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to May 2009.
Selection criteria
Randomised, double blind, placebo-controlled trials of single dose orally administered ibuprofen (any formulation) in adults with moderate to severe acute postoperative pain.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number-needed-to-treat-to-benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected.
Main results
Seventy-two studies compared ibuprofen and placebo (9186 participants). Studies were predominantly of high reporting quality, and the bulk of the information concerned ibuprofen 200 mg and 400 mg. For at least 50% pain relief compared with placebo the NNT for ibuprofen 200 mg (2690 participants) was 2.7 (2.5 to 3.0) and for ibuprofen 400 mg (6475 participants) it was 2.5 (2.4 to 2.6). The proportion with at least 50% pain relief was 46% with 200 mg and 54% with 400 mg. Remedication within 6 hours was less frequent with higher doses, with 48% remedicating with 200 mg and 42% with 400 mg. The median time to remedication was 4.7 hours with 200 mg and 5.4 hours with 400 mg. Sensitivity analysis indicated that pain model and ibuprofen formulation may both affect the result, with dental impaction models and soluble ibuprofen salts producing better efficacy estimates. Adverse events were uncommon, and not different from placebo.
Authors’ conclusions
The very substantial amount of high quality evidence demonstrates that ibuprofen is an effective analgesic in treating postoperative pain. NNTs for 200 mg and 400 mg ibuprofen did not change significantly from the previous review even when a substantial amount of new information was added. New information is provided on remedication.
PMCID: PMC4171980  PMID: 19588326
Administration, Oral; Analgesics, Non-Narcotic [* administration & dosage; adverse effects]; Ibuprofen [* administration & dosage; adverse effects]; Pain, Postoperative [* drug therapy]; Randomized Controlled Trials as Topic; Adult; Humans
23.  Combined isosorbide dinitrate and ibuprofen as a novel therapy for muscular dystrophies: evidence from Phase I studies in healthy volunteers 
We designed two Phase I studies that assessed healthy volunteers in order to evaluate the safety and to optimize the dosing of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a nonsteroidal antiinflammatory drug. We designed these studies with the aim of designing a Phase II trial to evaluate the drugs’ efficacy in patients affected by Duchenne muscular dystrophy. For the first trial, ISOFEN1, a single-dose, randomized-sequence, open-label, active control, three-treatment cross-over study, was aimed at comparing the pharmacokinetics of ibuprofen 200 mg and isosorbide dinitrate 20 mg when given alone and concomitantly. The pharmacokinetics of ibuprofen given alone versus ibuprofen given concomitantly with isosorbide dinitrate were similar, as documented by the lack of statistically significant differences in the main drug’s pharmacokinetic parameters (time to maximal concentration [Tmax], maximal concentration [Cmax], area under the curve [AUC]0–t, and AUC0–∞). Similarly, we found that the coadministration of ibuprofen did not significantly affect the pharmacokinetics of isosorbide dinitrate. No issues of safety were detected. The second trial, ISOFEN2, was a single-site, dose titration study that was designed to select the maximum tolerated dose for isosorbide dinitrate when coadministered with ibuprofen. Eighteen out of the 19 enrolled subjects tolerated the treatment well, and they completed the study at the highest dose of isosorbide dinitrate applied (80 mg/day). One subject voluntarily decided to reduce the dose of isosorbide dinitrate from 80 mg to 60 mg. The treatment-related adverse events recorded during the study were, for the large majority, episodes of headache that remitted spontaneously in 0.5–1 hour – a known side effect of isosorbide dinitrate. These studies demonstrate that the combination of isosorbide dinitrate and ibuprofen does not lead to pharmacokinetic interactions between the two drugs; they also demonstrate that the combination of isosorbide dinitrate and ibuprofen has optimal tolerability and safety profiles that are similar to those previously reported for isosorbide dinitrate and ibuprofen given alone.
PMCID: PMC4018313  PMID: 24851040
coadministration; pharmacokinetic profile; adverse events; ibuprofen; isosorbide dinitrate
24.  Randomized comparative trial of efficacy of paracetamol, ibuprofen and paracetamol-ibuprofen combination for treatment of febrile children 
Paracetamol and ibuprofen are widely used for fever in children as monotherapy and as combined therapy. None of the treatments is proven clearly superior to others. Hence, the study was planned to compare the efficacy of paracetamol, ibuprofen and paracetamol-ibuprofen combination for treatment of febrile children.
Materials and Methods:
This was an investigator blind, randomized, comparative, parallel clinical trial conducted in 99 febrile children, 6 months to 12 years of age, allocated to three groups. First group received paracetamol 15 mg/kg, second group received ibuprofen 10 mg/kg and third group received both paracetamol and ibuprofen, all as a single dose by the oral route. Patients were followed-up at intervals of 1, 2, 3 and 4 h post dose by tympanic thermometry.
Mean tympanic temperature after 4 h of drug administration was significantly lower in the combination group compared with paracetamol group (P < 0.05); however, the difference was not clinically significant (<1°C). The rate of fall of temperature was highest in the combination group. Number of afebrile children any time post dose until 4 h was highest in the combination group. Difference between combination and paracetamol was significant for the 1st h (P = 0.04). Highest fall of temperature was noted in the 1st h of drug administration in all the groups. No serious adverse events were observed in any of the groups.
Paracetamol and ibuprofen combination caused quicker temperature reduction than either paracetamol or ibuprofen alone. If quicker reduction of body temperature is the desired goal of therapy, the use of combination of paracetamol + ibuprofen may be advocated.
PMCID: PMC3915365  PMID: 24551584
Children; combination therapy; fever; ibuprofen; paracetamol
25.  Double-Blind Randomized Trials of Single-Tablet Ibuprofen/High-Dose Famotidine vs. Ibuprofen Alone for Reduction of Gastric and Duodenal Ulcers 
We performed two 24-week double-blind trials (REDUCE-1 and -2 (Registration Endoscopic Studies to Determine Ulcer Formation of HZT-501 Compared with Ibuprofen: Efficacy and Safety Studies)) to assess whether double-dose famotidine given in a single-tablet combination with ibuprofen (HZT-501) significantly reduces gastric and duodenal ulcers as compared with ibuprofen.
Patients (40–80 years) requiring daily non-steroidal anti-inflammatory drugs (NSAIDs) for ≥6 months with no prior ulcer complications, negative H. pylori stool test, and baseline endoscopy showing no ulcers and <5 erosions were randomly assigned in a 2:1 ratio to HZT-501 or identical-appearing ibuprofen 800 mg tablets thrice daily. Study endoscopies were done at 8, 16, and 24 weeks. After unblinding and initial analyses, 12 patients were found to be misclassified as having gastric ulcers based on the adjudication of endoscopy reports, and analyses were re-run.
In REDUCE-1, the primary end point analysis of gastric ulcers at 24 weeks with HZT-501 vs. ibuprofen was 12.7% vs. 22.9% (P=0.0044) in the post-adjudication analysis. In REDUCE-2, the primary end point analysis of upper gastrointestinal (GI) ulcers was 13.0% vs. 20.5% (P=0.0587) in the post-adjudication analysis. Prespecified pooled analyses showed significantly fewer gastric (12.5% vs. 20.7%) and duodenal ulcers (1.1% vs. 5.1%) with HZT-501 vs. ibuprofen. Proportional hazards analysis of multiple potential risk factors showed the risk ratio of upper GI ulcers with HZT-501 vs. ibuprofen was 0.46, 95% confidence interval was 0.34–0.61.
Combined results of the REDUCE studies indicate that double-dose famotidine plus ibuprofen, given as a combination tablet, decreases endoscopic upper GI ulcers as compared with ibuprofen alone.
PMCID: PMC3321505  PMID: 22186979

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