Dental Surgery Post-op Pain Is Treated More Effectively With Ibuprofen-Acetaminophen Combination than Medications Containing Narcotics

Date: 
09/01/2013

This study was designed to compare the efficacy and tolerability of a novel single-tablet combination of ibuprofen and acetaminophen with that of an ibuprofen/codeine combination and an acetaminophen/codeine combination. The pain model was the third molar extraction model of postoperative acute pain.

The study by Daniels, et al, was reported in the journal Pain in 2011. It was looking for alternative analgesics to codeine for postoperative pain management. Due to adverse effects associated with codeine, many patients either cannot or prefer not to take this narcotic. Thus, there was a need to find an alternative effective analgesic for use in combination therapy.

The study included 678 subjects randomized into the 5 study treatment groups:

  1. 400 mg ibuprofen/1000 mg acetaminophen
  2. 200 mg ibuprofen/500 mg acetaminophen
  3. 400 mg ibuprofen/25.6 mg codeine
  4. 1000 mg acetaminophen/30 mg codeine
  5. Placebo

The following table summarizes the results obtained in the 5 treatment arms:

Table: Comparative Results of Pain Relief

  1. 400 mg ibuprofen/1000 mg acetaminophen was more efficacious than placebo, acetaminophen/codeine and the ibuprofen/codeine.
  2. 200 mg ibuprofen/500 mg acetaminophen was superior to acetaminophen/codeine and non-inferior to ibuprofen/codeine combination.
  3. 400 mg ibuprofen/1000 mg acetaminophen was more efficacious than 200 mg ibuprofen/500 mg acetaminophen.
  4. Ibuprofen/codeine combination was more efficacious than acetaminophen/codeine combinations, and both were more efficacious than placebo.

Adverse events

During the study, 6 adverse events occurred in at least 5% of subjects in at least 1 of the 5 treatment groups. The 6, in order of overall incidence, were nausea, vomiting, headache, dizziness, alveolar osteitis and body temperature increase. The adverse events were significantly less frequent in the ibuprofen/acetaminophen groups compared to the codeine combinations.

Methods

Patients that were included were at least 16 years old, had at least 3 impacted third molars (2 of which had to be mandibular), and experienced moderate to severe postoperative pain of at least 5 or greater on a 10 point visual analog scale (VAS) within 6 hours of completion of surgery.

Each treatment consisted of 2 white tablets of a similar size and was administered as one oral dose, taken with water, after patients rated their pain intensity as moderate or severe on the VAS scale.

Rescue medication was available at any time post-dosing. If a rescue drug was needed within the first 4 hours after taking study medication, tramadol 100 mg (Ultram) was given. If a second dose was required within this 4 hour time frame, ketorolac (Toradol) 30 mg intramuscular was given. If rescue medication was needed after the first 4 hours, hydrocodone/acetaminophen (Lortab) or tramadol was given.

Efficacy assessments

Experiences were recorded by subjects under supervision at 0.25, 0.5, 0.75, 1, 1.5, and 2 hours; hourly thereafter up to 12 hours post-dose; and just prior to rescue medication (if applicable). In response to the question "What is your pain level at this time?" the level of pain was rated on a 4-point rating with 0=no pain, 1=mild pain, 2= moderate pain and 3=severe pain. Pain level was also rated, in response to the instruction "Indicate with a line on the scale your pain at this time," on a horizontal visual analog scale labeled as No Pain 0 as the left anchor and Worst Pain 10 as the right anchor.

In response to the question "How much relief have you had from your starting pain?" pain relief was rated on a 5-point scale as 0=no pain relief, 1=a little, 2=some pain relief, 3=a lot and 4=complete pain relief.

Adverse events were recorded from the time of dosing until completion of a follow-up visit.

The following table lists the averages of the responses of pain relief versus treatment over the time periods. The ibuprofen 400 mg/acetaminophen 1000 mg treatment showed the best pain relief over the 8 hour period:

Table: Pain Relief Rankings

Pain relief ranking- hours after taking drug (0=no relief; 4=complete relief)

Treatment 0.5 1 2 4 6 8
Ibu 400 mg/acet 1000 mg 1.7 2.5 2.8 2.8 2.5 1.8
Ibu 200 mg/acet 500 mg 1.7 2.5 2.7 2.6 2.0 1.4
Ibu 400 mg/codeine 25.6 mg 1.7 2.5 2.6 2.4 1.9 1.4
Acet 1000 mg/codeine 30 mg 1.7 2.5 2.5 1.8 1.0 0.7
Placebo 0.4 0.5 0.5 0.4 0.3 0.3

The following table shows the percent of subjects requiring rescue medications anytime within a 5-hour window after taking the treatment drug. As expected, most subjects taking the placebo (90%) needed rescue medications to treat the pain. On the other end of the scale, only 15% of those receiving ibuprofen 400 mg/acetaminophen 1000 mg needed rescue medications.

Table: Subjects needing rescue medications

Percent of subjects needing rescue medications anytime between 1 and 6 hours after taking treatment drug

Treatment Percentage (%)
Placebo 90%
Acet 1000 mg/codeine 30 mg 55%
Ibu 400 mg/codeine 25.6mg 30%
Ibu 200 mg/acet 500 mg 26%
Ibu 400 mg/acet 1000 mg 15%

Discussion of the study

The entire report can be found at:

Daniels, S.E., et al. "A randomized, 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; 152:632-642.

According to the authors, ibuprofen and acetaminophen differ in their actions. Ibuprofen acts by inhibiting cyclooxygenase enzymes COX-1 and COX-2 and subsequent synthesis of prostaglandins within injured tissues in the peripheral. In contrast, acetaminophen appears to inhibit a subclass of cyclooxygenase enzymes in the central nervous system. The differences in their mode of actions suggest that they may complement each other and that enhanced analgesic effects without increased toxicity may be obtained with combination therapy over mono-therapy. The rationale for combined analgesia is that enhanced pain relief can be potentially achieved without opioids and with reduced side effects. The ibuprofen/acetaminophen combination provided highly effective analgesia for postoperative acute dental pain that was comparable with or superior to codeine combinations currently indicated for strong pain. The ranking of all five treatments in terms of pain relief from best to worst was:

  1. 400 mg ibuprofen/1000 mg acetaminophen
  2. 200 mg ibuprofen/500 mg acetaminophen
  3. 400 mg ibuprofen/25.6 mg codeine
  4. 1000 mg acetaminophen/30 mg codeine
  5. placebo

An earlier report on ibuprofen-acetaminophen combination and dental pain relief

An earlier report by Mehlisch, et al, published in the journal Clinical Therapeutics in 2010 described the efficacy of the combination of over-the-counter ibuprofen and acetaminophen. The study evaluated the analgesic benefits of concurrent ibuprofen and 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, 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 end points. 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.

Details of this study are found in October 2011 Lexicomp newsletter archives.

The published report can be found at:

Mehlisch, D.R.; Aspley, S.; Daniels, S.E.; Bandy, D.P. "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." Clinical Therapeutics, 2010; 32:882-895.

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