Over-the-Counter Ibuprofen and Acetaminophen in Combination are Superior to Each Agent Alone in Treating Postoperative Pain

The first two reports (Derry, et al and Toms, et al) describe the efficacy of single doses of ibuprofen and single doses of acetaminophen for postoperative pain, compared to placebo in well-controlled trials. The third report (Mehlisch, et al) describes the analgesic benefits of the combination of the two agents (compared with each drug alone), again in well-controlled trials. These studies provide further evidence-based information for the rational use of over-the-counter pain relievers for postoperative dental pain.
Study #1 Assessing the efficacy of single dose over-the-counter ibuprofen
Derry C, Derry S, Moore RA, et al, “Single Dose Oral Ibuprofen for Acute Postoperative Pain in Adults,” Cochrane Database Syst Rev, 2009, July 8, (3) CD001548.
The objective of this study was to assess the analgesic efficacy of ibuprofen in single oral doses for moderate and severe postoperative pain in adults. The method was to search the Cochrane Library, CENTRAL, MEDLINE, EMBASE, and the Oxford Pain Relief Database for studies to May, 2009. Selection of studies considered for review was based on randomized, double-blind, placebo-controlled trials of single-dose orally administered ibuprofen in adults with moderate to severe acute postoperative pain. Pain relief or pain intensity data were extracted and converted to outcomes of numbers 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. The number of participants using rescue medication over specified time periods, and the time to rescue medication, were sought as additional measures of efficacy. Finally, information on adverse events and withdrawals was collected.
Results of the Derry, et al, study
The studies reviewed totaled 72 and included 9,186 participants, in which ibuprofen was compared to placebo. The majority of the studies used ibuprofen at 200 mg and 400 mg doses.
For at least 50% pain relief compared with placebo, the number-needed-to-treat-to-benefit for ibuprofen 200 mg (2,690 participants) was 2.7 (2.5 to 3.0) and for ibuprofen 400 mg (6,475 participants) it was 2.6 (2.4 to 2.6).
The proportion with at least 50% pain relief was 46% with 200 mg ibuprofen and 54% with 400 mg ibuprofen. Remedication within 6 hours was less frequent with higher doses, with 48% remedicating with 200 mg and 42% remedicating with 400 mg. The median time to remedication was 4.7 hours for 200 mg and 5.4 hours for 400 mg.
The studies using dental impaction pain models and soluble ibuprofen salts (liquid gel capsule formulations) produced better efficacy estimates. Adverse events were uncommon and no different from placebo.
The authors concluded a substantial amount of high quality evidence demonstrated that over-the-counter ibuprofen is an effective pain reliever in treating postoperative pain.
Study #2 Assessing the efficacy of single dose over-the-counter acetaminophen
Toms L, McQuay HJ, Derry S, et al, “Single Dose Oral Paracetamol (Acetaminophen) for Postoperative Pain in Adults,” Cochrane Database Syst Rev, 2008, Oct 8, (4) CD004602.
The objective of this study was to assess the efficacy of single dose oral acetaminophen for the treatment of acute postoperative pain. The method was to search the Cochrane Library, MEDLINE, EMBASE, the Oxford Pain Relief Database, and reference lists of articles to update data from an existing version of the review. Selection of studies considered for review was based on randomized, double-blind, placebo-controlled trials of acetaminophen for acute postoperative pain in adults.
Area under the “pain relief versus time” curve was used to derive the proportion of participants with acetaminophen or placebo experiencing at least 50% pain relief over 4 to 6 hours, using validated equations. Number-needed-to-treat-to-benefit was calculated. The proportion of participants using rescue analgesia over a specified time period and time to use were sought as measures of duration of analgesia. Information on adverse events and withdrawals was also collected.
Results of the Toms, et al, study
Fifty-one studies with 5,762 participants were included; of those who took acetaminophen or placebo, 3,277 participants were treated with a single oral dose of acetaminophen and 2,425 with placebo. About half of the participants treated with acetaminophen at standard doses achieved at least 50% pain relief over 4 to 6 hours compared with about 20% treated with placebo.
Number-needed-to-treat-to-benefit for at least 50% pain relief over 4 to 6 hours following a single 500 mg dose of acetaminophen was 3.5 (2.7 to 4.8); following a single 600 to 650 mg dose it was 4.6 (3.9 to5.5); following a single dose of 975 to 1000 mg it was 3.6 ( 3.4 to 4.0).
About half the participants taking acetaminophen needed additional analgesia over 4 to 6 hours compared with about 70% with placebo.
Five people would need to be treated with 1000 mg acetaminophen, the most commonly used dose, to prevent one needing rescue medication over 4 to 6 hours, who would have needed it with placebo.
Reported adverse events were mild and transient, and occurred at similar rates with 1000 mg acetaminophen and placebo. No serious adverse events were reported.
The authors concluded that a single dose of acetaminophen provided effective analgesia for about half of the patients with acute postoperative pain for a period of about 4 hours and is associated with few, mainly mild, adverse events.
Study #3 Assessing the efficacy of the combination of over-the-counter ibuprofen and acetaminophen
Mehlisch DR, Aspley S, Daniels SE, et al, “Comparison of the Analgesic Efficacy of Concurrent Ibuprofen and Paracetamol With Ibuprofen or Paracetamol Alone in the Management of Moderate to Severe Acute Postoperative Dental Pain in Adolescents and Adults: A Randomized, Double-blind, Placebo-controlled, Parallel-group, Single-dose, Two-center, Modified Factorial Study,” Clin Ther, 2010, 32:882-95.
This study was done to test the hypothesis that combination analgesics may offer improved analgesic efficacy, particularly for moderate to severe pain. The authors evaluated the analgesic benefits of concurrent ibuprofen and paracetamol (acetaminophen), compared with each drug used alone, in the management of acute postoperative dental pain.
Methods
The study enrolled healthy patients, ages 16 to 40 years, undergoing surgical removal of 3 to 4 impacted molars. The protocol was a randomized, double-blind, placebo-controlled, parallel-group, single-dose, two center study. Patients were randomly assigned to ibuprofen 400 mg/acetaminophen 1000 mg combination, ibuprofen 200 mg/acetaminophen 500 mg combination, ibuprofen 400 mg alone, acetaminophen 1000 mg alone, or placebo when the postoperative pain reached moderate to severe intensity.
The primary endpoint of efficacy was the sum of pain relief and pain intensity differences from 0 to 8 hours. Secondary endpoints included total pain relief, sum of pain intensity differences, and sum of pain intensity differences on the visual analog scale at various time endpoints. Other analgesic measures included peak effect, onset and duration of effect, and patients’ overall assessment of treatment. The tolerability of study medicines was also assessed in terms of frequency and nature of adverse events.
Results of the Mehlisch, et al, study
A total of 234 patients were randomly assigned to treatment and included in the intent-to-treat population.
Results for the primary endpoint
For the sum of pain relief and pain intensity differences, the group receiving the combination of ibuprofen 400 mg/acetaminophen 1000 mg had significantly better mean scores compared with ibuprofen 400 mg alone, acetaminophen 1000 mg alone and the combination of ibuprofen 200 mg/acetaminophen 500 mg.
For the sum of pain relief and pain intensity differences, the group receiving the combination of ibuprofen 200 mg/acetaminophen 500 mg had significantly better mean scores compared with acetaminophen 1000 mg alone, but not compared to ibuprofen 400 mg alone.
Results for secondary endpoints
Ibuprofen 400 mg/acetaminophen 1000 mg was associated with significantly better scores than was single agent therapy for total pain relief, sum of pain intensity differences, and sum of pain intensity differences on the visual analog scale at all time intervals, and for sum of pain relief and pain intensity differences from 4 to 6 hours.
A breakdown of the Mehlisch, et al, data showed the following:
Time to the first confirmed perceptible pain relief for each treatment was:
Ibuprofen 400 mg/acetaminophen 1000 mg: 23 minutes
Ibuprofen 200 mg/acetaminophen 500 mg: 22 minutes
Ibuprofen 400 mg: 49 minutes
Acetaminophen 1000 mg: 25 minutes
Placebo: 98 minutes
Time to the first meaningful pain relief for each treatment was:
Ibuprofen 400 mg/acetaminophen 1000 mg: 94 minutes
Ibuprofen 200 mg/acetaminophen 500 mg: 74 minutes
Ibuprofen 400 mg: 124 minutes
Acetaminophen 1000 mg: 141 minutes
Placebo: 133 minutes
Time to pain half gone for each treatment was:
Ibuprofen 400 mg/acetaminophen 1000 mg: 70 minutes
Ibuprofen 200 mg/acetaminophen 500 mg: 86 minutes
Ibuprofen 400 mg: 114 minutes
Acetaminophen 1000 mg: 135 minutes
Placebo: 229 minutes
There were significant differences in favor of all active treatments versus placebo for all efficacy endpoints. Adverse events were similar across treatments, with the most frequent being nausea [26.1% (61/234)], vomiting [18.8% (44/234)], headache [10.3% (24/234)], and dizziness [8.1% (19/234)].
The authors concluded that concurrent ibuprofen and acetaminophen appeared to provide significantly better analgesic efficacy compared with either drug alone for management of acute postoperative dental pain.