Background & Aims

The opioid epidemic has expanded interest in comparative effectiveness of non-opioids for acute and chronic pain. Third molar dental extraction surgery is a common model for testing of new treatments for acute pain. Registration trials submitted to the Food and Drug Administration (FDA) provide a unique resource for individual participant data (IPD) on some analgesics and an opportunity to compare their relative efficacy profiles beyond the standard meta-analytic approaches.

A contract with the FDA provided us access to 13 randomized double-blind trials of 6 oral and 4 IV products. We harmonized available IPD data to examine time to onset, the maximum proportion of responders, the duration of effect, and created the novel Group Response Outcome Over Time (GROOT) summary statistic using the cut-off of ?50% reduction in pain as the clinically important cut-off. A novel process for this comparison will be presented in graphic and table form.

Methods

1) Using a novel outcome for the efficacy of a drug over time – the Group Response Outcome (GRO) – we show the average proportion of patients achieve >50% improvement in pain from baseline by study drug and dose as a visual comparison of onset rate, rate of response, and duration of response. The area under the GRO curve over time – the GROOT – represents the proportion of time participants who achieve a meaningful response remain at or above that level. We present a GROOT that was calculated for 6 hours in our table.

2) The maximum rate of response is the maximum value for the GRO curve.

3) We estimate time-to-onset as the median value and 25%-75% percentiles of the time each participant takes to achieve ?50% pain improvement from baseline in those participants that reach this level.

4) The duration of effect is the sum of all the time a subject reports a 50% or more pain improvement across the study period. The median and 25%-75% percentiles are presented.

Results

Efficacy (value 0-1) 2)Max3)Onset in Min. 4)Duration in Min.
DRUGRoute n1)GROOTlowerupper GRO Medianq25q75 Median q25 q75

AcetaminoIV234 0.390.340.43 0.53 151330 195119321
DiclofenacIV205 0.640.590.68 0.85 301545 3301951260
KetorolacIV47 0.720.630.81 0.83 301545 3973041380
MeloxicamIV150 0.650.590.71 0.76 432860 1048 570 1397
Placebo IV281 0.090.060.12 0.12 311568 12140602

AcetaminoPO276 0.370.330.42 0.48 593063 270120453
Acetamino/PO554 0.63 0.6 0.66 0.77 603090 418300568
Ibuprof
CelecoxibPO102 0.4 0.330.47 0.56 9060120363300453
DiclofenacPO100 0.51 0.440.57 0.73 904590 360181609
IbuprofenPO142 0.57 0.51 0.62 0.73 6060120 457315660
IndomethPO101 0.330.260.39 0.47 9060151363270393
PlaceboPO3580.090.070.110.141056018024398529

Conclusions

Our results demonstrate a high degree of efficacy for IV meloxicam, diclofenac, and ketorolac with a maximum responder rates (i.e., those reaching ?50% – MaxGRO) of 76%, 85% and 83% respectively but onset times of 43min and a duration of >17 hours for meloxicam. Diclofenac and ketorolac had onsets of 30 minutes and 6-hour durations. Onset for acetaminophen and ibuprofen was 60 minutes with durations of 6-8 hours, vs onset of 15 minutes for IV acetaminophen, but the duration as only 3 hours.

The area under the GRO curve (GROOT) is impacted by all three other characteristics. It was calculated for 6 hours here. IV diclofenac, meloxicam ketorolac, and oral acetaminophen/ ibuprofen combination had values > 0.63 while celecoxib, indomethacin, and tramadol were substantially lower. These drug-drug relationships remained essentially unchanged in our sensitivity analysis subtracting the placebo group from each comparison. The choice of medication will depend on patient requirements.

References

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Presenting Author

John T. Farrar

Poster Authors

John Farrar

MD, PhD

Univ of PA

Lead Author

E-mail

Ian Delorey

MS

University of Pennsylvania

Lead Author

E-mail

Jennifer S. Gewandter

PhD

University of Rochester

Lead Author

E-mail

Ian Gilron

Queens University, Canada

Lead Author

E-mail

Christopher Miller

MS

University of Pennsylvania

Lead Author

E-mail

Warren Bilker

University of Pennsylvania

Lead Author

E-mail

Charles Argoff

MD

Albany Medical Health System

Lead Author

E-mail

Russell Bell

MD

University of Pennsylvania

Lead Author

E-mail

Katherine Theken

University of Pennsylvania

Lead Author

E-mail

Jennifer Haythornthwaite

United States Association for the Study of Pain

Lead Author

E-mail

Topics

  • Evidence, Clinical Trials, Systematic Review, Guidelines, and Implementation Science